As with other mitochondrial respiratory chain components, marked clinical and genetic heterogeneity is observed in patients with a cytochrome c oxidase deficiency. This constitutes a considerable diagnostic challenge and raises a number of puzzling questions. So far, pathological mutations have been reported in more than 30 genes, in both mitochondrial and nuclear DNA, affecting either structural subunits of the enzyme or proteins involved in its biogenesis. In this review, we discuss the possible causes of the discrepancy between the spectacular advances made in the identification of the molecular bases of cytochrome oxidase deficiency and the lack of any efficient treatment in diseases resulting from such deficiencies. This brings back many unsolved questions related to the frequent delay of clinical manifestation, variable course and severity, and tissue-involvement often associated with these diseases. In this context, we stress the importance of studying different models of these diseases, but also discuss the limitations encountered in most available disease models. In the future, with the possible exception of replacement therapy using genes, cells or organs, a better understanding of underlying mechanism(s) of these mitochondrial diseases is presumably required to develop efficient therapy.

CYTOCHROME OXIDASE, AN OVERVIEW OF STRUCTURE, FUNCTION AND REGULATION

Cytochrome c oxidase (COX; EC 1.9.3.1) is the unique terminal oxidase of the mitochondrial respiratory chain (RC) in mammals (Figure 1). COX also referred to as complex IV is made up of 13 subunits that catalyse the transfer of electrons from ferro-cytochrome c to molecular oxygen. This exergonic reaction is coupled to proton transfer across the inner membrane, which contributes to the electrochemical gradient used for ATP synthesis (Figure 1A). The electrochemical gradient is also crucial for preserving the capacity of mitochondria to exchange metabolites and ions with the surrounding cytosol and other organelles.

COX location in the RC and activity assay in human skin fibroblasts

Figure 1
COX location in the RC and activity assay in human skin fibroblasts

(A) Schematic representation of the RC in the inner mitochondrial membrane showing the interaction of COX (complex IV) with complexes I and III in a super-complex (respirasome). The site of action of specific inhibitors is indicated in red. The green arrow shows the alternative oxidase (AOX) by-pass, which when expressed in COX-defective human mitochondria or flies rescues their various phenotypes. The assay of COX with externally added cytochrome c requires the permeabilization of the outer membrane. (B) COX is assayed spectrophotometrically by measuring using a double-wavelength spectrophotometer (550–540 nm) the oxidation of reduced cytochrome c in skin fibroblasts permeabilized by two successive freeze/thaw cycles. The reaction is first order with respect to substrate concentration and is thus diminished by half when half of the reduced cytochrome c is consumed. Subsequent sequential addition of rotenone, cyanide, oxidized cytochrome c and succinate measures reduction in cytochrome c, first by the succinate-cytochrome c reductase (CII plus CIII). The activity is essentially rate controlled by CII and can be inhibited by malonate, a competitive inhibitor of CII. Further addition of glycerol-3 phosphate measures the activity from the glycerol-3 phosphate dehydrogenase (G3Pdh) to CIII. This activity can be selectively inhibited by iGP1 [143]. Finally, addition of decylubiquinol in the presence of EDTA is used to measure antimycin-sensitive CIII activity. Abbreviations: The RC complexes are abbreviated as, CI, CII, CIII, CIV, and the ATP synthase as CV; c, cytochrome c; Ddh, the dihydroorotate dehydrogenase which catalyse the production of uridine, an essential step for the synthesis of nucleic acids; EDTA, ethylenediamine tetraacetic acid; ETF, the electron transfer flavoprotein involved in the oxidation of fatty acids; G3Pdh, the glycerol 3-phosophate dehydrogenase; GCCR, iGP1-sensitive glycerol 3-phosphate; IM, inner membrane; KCN, potassium cyanide; OM, outer membrane; QCCR, antimycin-sensitive decylubiquinol-cytochrome c reductase; SCCR, malonate-sensitive cytochrome c reductase; UQ, ubiquinone 50, or coenzyme Q10.

Figure 1
COX location in the RC and activity assay in human skin fibroblasts

(A) Schematic representation of the RC in the inner mitochondrial membrane showing the interaction of COX (complex IV) with complexes I and III in a super-complex (respirasome). The site of action of specific inhibitors is indicated in red. The green arrow shows the alternative oxidase (AOX) by-pass, which when expressed in COX-defective human mitochondria or flies rescues their various phenotypes. The assay of COX with externally added cytochrome c requires the permeabilization of the outer membrane. (B) COX is assayed spectrophotometrically by measuring using a double-wavelength spectrophotometer (550–540 nm) the oxidation of reduced cytochrome c in skin fibroblasts permeabilized by two successive freeze/thaw cycles. The reaction is first order with respect to substrate concentration and is thus diminished by half when half of the reduced cytochrome c is consumed. Subsequent sequential addition of rotenone, cyanide, oxidized cytochrome c and succinate measures reduction in cytochrome c, first by the succinate-cytochrome c reductase (CII plus CIII). The activity is essentially rate controlled by CII and can be inhibited by malonate, a competitive inhibitor of CII. Further addition of glycerol-3 phosphate measures the activity from the glycerol-3 phosphate dehydrogenase (G3Pdh) to CIII. This activity can be selectively inhibited by iGP1 [143]. Finally, addition of decylubiquinol in the presence of EDTA is used to measure antimycin-sensitive CIII activity. Abbreviations: The RC complexes are abbreviated as, CI, CII, CIII, CIV, and the ATP synthase as CV; c, cytochrome c; Ddh, the dihydroorotate dehydrogenase which catalyse the production of uridine, an essential step for the synthesis of nucleic acids; EDTA, ethylenediamine tetraacetic acid; ETF, the electron transfer flavoprotein involved in the oxidation of fatty acids; G3Pdh, the glycerol 3-phosophate dehydrogenase; GCCR, iGP1-sensitive glycerol 3-phosphate; IM, inner membrane; KCN, potassium cyanide; OM, outer membrane; QCCR, antimycin-sensitive decylubiquinol-cytochrome c reductase; SCCR, malonate-sensitive cytochrome c reductase; UQ, ubiquinone 50, or coenzyme Q10.

The three largest subunits of COX are encoded in mitochondrial DNA (mtDNA). These core subunits contain all the heme haem and metal prosthetic groups needed for catalysis. The remaining ten subunits are products of nuclear genes that are translated as pre-proteins on cytosolic ribosomes, imported to different compartments of mitochondria by the TIM (translocase of the inner membrane) and TOM (translocase of the outer membrane) transport machineries and possibly modified before entering the COX-assembly pathway [1,2]. A large number of factors, sometimes specific to COX assembly and in other cases with broader specificity, are known to facilitate the various steps of COX assembly and its incorporation into the RC super-complexes, also referred to as the respirasome (Figures 2 and 3).

Synthesis and assembly of COX subunits

Figure 2
Synthesis and assembly of COX subunits

A scheme summarizing what is presently known about the pathways for the integrated synthesis and assembly of COX subunits expressed from the nuclear and mitochondrial genomes. Protein subunits translated on cytosolic ribosomes with N-terminal presequences are first transported by the outer membrane TOM complex and are subsequently matured and sorted by the TIM and MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) machineries to the intermembrane space, inner membrane or matrix where they interact with partner proteins to form assembly intermediates [144146]. Subunits encoded by mtDNA genes are translated on mitochondrial ribosomes attached to the matrix side of the inner membrane. Following insertion into the inner membrane by Oxa1 they interact with their nucleo-cytoplasmic partners to form subcomplexes that subsequently assemble into COX. The overall process is assisted by numerous proteins acting in transport, translation, chaperoning of different assembly steps. Oxa1 is also involved in the biogenesis of other RC complexes. Some of the genes coding for ancillary factors (indicated in red) have been found to be mutated in COX deficient patients. IM, inner membrane; OM, outer membrane; 1, 2, 4, 5a, COX subunits (purple).

Figure 2
Synthesis and assembly of COX subunits

A scheme summarizing what is presently known about the pathways for the integrated synthesis and assembly of COX subunits expressed from the nuclear and mitochondrial genomes. Protein subunits translated on cytosolic ribosomes with N-terminal presequences are first transported by the outer membrane TOM complex and are subsequently matured and sorted by the TIM and MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) machineries to the intermembrane space, inner membrane or matrix where they interact with partner proteins to form assembly intermediates [144146]. Subunits encoded by mtDNA genes are translated on mitochondrial ribosomes attached to the matrix side of the inner membrane. Following insertion into the inner membrane by Oxa1 they interact with their nucleo-cytoplasmic partners to form subcomplexes that subsequently assemble into COX. The overall process is assisted by numerous proteins acting in transport, translation, chaperoning of different assembly steps. Oxa1 is also involved in the biogenesis of other RC complexes. Some of the genes coding for ancillary factors (indicated in red) have been found to be mutated in COX deficient patients. IM, inner membrane; OM, outer membrane; 1, 2, 4, 5a, COX subunits (purple).

Maturation and insertion of COX into the RC

Figure 3
Maturation and insertion of COX into the RC

Mammalian COX exists as a dimer. Each monomer consists of 13 different subunits. At present human mutations leading to a COX deficiency have been identified in six structural subunits including the three mtDNA-encoded core proteins (in red) and in nine ancillary proteins (also indicated in red). The catalytic activity of COX depends on haem a, a3 and two copper centres (CuA and CuB) linking COX biosynthesis to both copper and haem metabolism. Maturation of COX active centres involves a number of factors, some of which have also been found mutated in COX deficient patients (denoted in red). IM, inner membrane; OM, outer membrane; 1, 2, 4, 5a, 5c, 6a, 6b, 6c, 7a, 7b, 8, the different COX subunits; CI, CII, CIII, CIV, the various complexes of the RC.

Figure 3
Maturation and insertion of COX into the RC

Mammalian COX exists as a dimer. Each monomer consists of 13 different subunits. At present human mutations leading to a COX deficiency have been identified in six structural subunits including the three mtDNA-encoded core proteins (in red) and in nine ancillary proteins (also indicated in red). The catalytic activity of COX depends on haem a, a3 and two copper centres (CuA and CuB) linking COX biosynthesis to both copper and haem metabolism. Maturation of COX active centres involves a number of factors, some of which have also been found mutated in COX deficient patients (denoted in red). IM, inner membrane; OM, outer membrane; 1, 2, 4, 5a, 5c, 6a, 6b, 6c, 7a, 7b, 8, the different COX subunits; CI, CII, CIII, CIV, the various complexes of the RC.

Complex IV of the mammalian RC has been shown to interact with complexes I and III with variable stoichiometry to form the respirasome [3,4]. This organization of the RC into a respirasome, de facto, isolates kinetic pools of electron carriers, including mobile carriers such as ubiquinone [5], to efficiently channel electrons supplied by various dehydrogenases of mitochondria to the appropriate segments of the RC [6]. In the context of mitochondrial diseases, a primary loss of COX may have secondary effects on the organization of the respirasome thereby eliciting more complex biochemical phenotypes [7,8].

In mammals, the composition of tightly bound subunits of the COX core is constant. However, the expression of several nuclear-encoded isoforms of one or more imported subunits may vary depending on the developmental stage and the tissue (Table 1; Figure 4). Indeed, extensive SDS-PAGE analyses together with immunological and/or sequencing data by the Kadenbach and Grossman groups have demonstrated the occurrence of several isoforms of the COX4, COX6A, COX6B, COX7A and COX8 [1,2] subunits that are variably expressed during fetal development in mammals [9] (Table 1; Figure 4). COX activity is regulated by the ATP/ADP ratio, which affects its phosphorylation status [10], and association of COX into dimers, as well as its interactions with cardiolipin [11] and other proteins [2]. Finally, beside the 13 tightly bound subunits observed by the Kadenbach group and later confirmed by the Yoshikawa group by X-ray crystallography [12], a more loosely bound 14th subunit product of the NDUFA4 gene was detected in stoichiometric amounts when analysed by BN-PAGE [13]. This idea gained support from the finding that a mutation in NDUFA4 results in a specific COX deficiency [14].

Table 1
The human cytochrome c oxidase subunits and isoforms
Subunit name and symbol Alternative names OMIM no. 
Cytochrome c oxidase subunit I; MTCO1 COI; COX1 516030 
Cytochrome c oxidase subunit II; MTCO2 COII; COX2 516040 
Cytochrome c oxidase subunit III; MTCO3 COIII; COX3 516050 
Cytochrome c oxidase, subunit IV, ISOFORM 1; COX4I1 COX4 123864 
Cytochrome c oxidase, subunit IV, ISOFORM 2; COX4I2 COX IV-2; COX4-2 607976 
Cytochrome c oxidase, subunit Va; COX5A  603773 
Cytochrome c oxidase, subunit Vb; COX5B  123866 
Cytochrome c oxidase, subunit VIa, POLYPEPTIDE 1; COX6A1 Liver isoform; COX6AL 602072 
Cytochrome c oxidase, subunit VIa, POLYPEPTIDE 2; COX6A2 Muscle isoform; COX6AH; COX6AM 602009 
Cytochrome c oxidase, subunit VIb POLYPEPTIDE 1; COX6B1  124089 
Cytochrome c oxidase, subunit VIb POLYPEPTIDE 2; COX6B2 Cancer/testis antigen 59 CT59 Not available 
Cytochrome c oxidase, subunit VIc; COX6C  124090 
Cytochrome c oxidase, subunit VIIa, POLYPEPTIDE 1; COX7A1 Muscle isoform; COX7AM 123995 
Cytochrome c oxidase, subunit VIIa, POLYPEPTIDE 2; COX7A2 Liver isoform 1; COX7AL; COX7AL1 123996 
Cytochrome c oxidase, subunit VIIb; COX7B  300885 
Cytochrome c oxidase, subunit VIIc; COX7C  603774 
Cytochrome c oxidase, subunit VIII; COX8  123870 
Subunit name and symbol Alternative names OMIM no. 
Cytochrome c oxidase subunit I; MTCO1 COI; COX1 516030 
Cytochrome c oxidase subunit II; MTCO2 COII; COX2 516040 
Cytochrome c oxidase subunit III; MTCO3 COIII; COX3 516050 
Cytochrome c oxidase, subunit IV, ISOFORM 1; COX4I1 COX4 123864 
Cytochrome c oxidase, subunit IV, ISOFORM 2; COX4I2 COX IV-2; COX4-2 607976 
Cytochrome c oxidase, subunit Va; COX5A  603773 
Cytochrome c oxidase, subunit Vb; COX5B  123866 
Cytochrome c oxidase, subunit VIa, POLYPEPTIDE 1; COX6A1 Liver isoform; COX6AL 602072 
Cytochrome c oxidase, subunit VIa, POLYPEPTIDE 2; COX6A2 Muscle isoform; COX6AH; COX6AM 602009 
Cytochrome c oxidase, subunit VIb POLYPEPTIDE 1; COX6B1  124089 
Cytochrome c oxidase, subunit VIb POLYPEPTIDE 2; COX6B2 Cancer/testis antigen 59 CT59 Not available 
Cytochrome c oxidase, subunit VIc; COX6C  124090 
Cytochrome c oxidase, subunit VIIa, POLYPEPTIDE 1; COX7A1 Muscle isoform; COX7AM 123995 
Cytochrome c oxidase, subunit VIIa, POLYPEPTIDE 2; COX7A2 Liver isoform 1; COX7AL; COX7AL1 123996 
Cytochrome c oxidase, subunit VIIb; COX7B  300885 
Cytochrome c oxidase, subunit VIIc; COX7C  603774 
Cytochrome c oxidase, subunit VIII; COX8  123870 

The non-overlapping clinical symptoms of COX deficiency and expression territories of COX subunits

Figure 4
The non-overlapping clinical symptoms of COX deficiency and expression territories of COX subunits

On the left are shown ubiquitously expressed subunits which when mutated result in a constellation of symptom but sparing numerous organs. The representations in the middle and on the right show that mutation in genes encoding subunits with more specific organ/tissue expression does not necessarily result in symptoms affecting the predicted organs. Subunits encoded in mtDNA are depicted in green. Genes with identified mutations in patients with COX deficiency are shown in yellow (or green).

Figure 4
The non-overlapping clinical symptoms of COX deficiency and expression territories of COX subunits

On the left are shown ubiquitously expressed subunits which when mutated result in a constellation of symptom but sparing numerous organs. The representations in the middle and on the right show that mutation in genes encoding subunits with more specific organ/tissue expression does not necessarily result in symptoms affecting the predicted organs. Subunits encoded in mtDNA are depicted in green. Genes with identified mutations in patients with COX deficiency are shown in yellow (or green).

GENETIC DISEASES CHARACTERIZED BY A COX DEFICIENCY

Patients with a COX deficiency can present surprisingly variable clinical phenotypes. As of now mutations in more than 20 mitochondrial and nuclear genes associated with COX deficiency are known to lead to a constellation of phenotypes. Parameters such as lactic acidosis in the blood or cerebro-spinal fluid, ragged-red fibres in adult skeletal muscle biopsies are hallmarks of mitochondrial diseases but they are not specific to COX deficiencies. The following circumstances may modulate the severity and clinical manifestations of a COX and more generally an RC mutation; a) the organs being affected (e.g. a heart specific COX defect is unlikely to change the general metabolic equilibrium of the organism), b) the severity of the deficiency (e.g. partial COX defect can have deleterious consequences, yet not significantly change the metabolic equilibrium under basal conditions), and c) the capacity to cope with a COX defect (e.g. the course of disease resulting from a given mutation often differ between patients). As a result, even the absence of typical manifestation of COX (or RC) deficiency should not exclude a clinical anamnesis by advertised clinician, which may justify proceeding to further investigation.

NEW METHODS, OLD QUESTIONS

The large scale screening with micro-chips identifying both mtDNA and nuclear gene mutations has been partially responsible for the steady increase in the number of identified mutations in patients suspected to have dysfunctional mitochondria (see MITOMAP for an update) [15]. Unfortunately, except for known or non-ambiguous mutations affecting COX-related genes, there currently is no simple way to ascribe a clinical phenotype to the reported base change even when the latter is in a gene of known function. Examples abound showing that the nature of the amino acid change, its location in the protein or its evolutionary conservation are not sufficient to establish pathogenicity. Consequently, a biochemical screen of the RC complexes function is usually required. COX activity can be conveniently assayed in virtually all human tissues and cells [16] (Figure 1B). It should be kept in mind, however, that the results obtained with tissue samples do not always lead to a correct identification of the underlying lesion. Indeed, errors can occur when the mutation shows a high degree of tissue-specific expression and therefore is not necessarily detectable in the particular sample analysed. Another source of ambiguity may arise with mutations causing an accumulation of mitochondria, thus compensating for the decrease in the enzyme and giving the impression of a normal activity. This is not uncommon, especially in the skeletal muscle but can be avoided by normalizing the activity of the deficient enzyme to another RC component or to a marker for mitochondrial mass (Figure 1B) [17].

HUMAN DISEASES CAUSED BY GENETICALLY DETERMINED COX DEFICIENCY

A sensible and useful way of classifying COX deficiencies takes into consideration their genetic origin. Indeed mutations in the same gene are expected to affect a common step or activity in the same tissue and consequently have a similar outcome. However, what is observed in patients is an impressive diversity of phenotypes independently of whether the mutation affects the biosynthesis/maturation of a mitochondrial or nucleus-encoded COX subunit or of its assembly into the mature complex and ultimately super-complex. A number of excellent reviews have been written on various aspects of COX deficiencies [1820] and databases are regularly updated incorporating the rapidly growing body of new information [15].

Mutations in mitochondrial COX genes

Numerous diseases resulting from mutations in the mitochondrial genes encoding MTCO1, MTCO2 and MTCO3 have been reported. The mutations in each of these three COX subunits have been associated with a variety of more or less severe phenotypes (Table 2). In addition, COX3 mutations have also been connected with Alzheimer disease [21] but this has been disputed as the underlying cause may be an overproduction of superoxides by the mitochondrial RC rather than by the COX deficiency [22].

Table 2
Mutations in COX-assembly and structural genes and their phenotypic consequences in human and animals [as in the text, for all cited species, human nomenclature has been used (HGNC)] [92]
Mutant gene Known clinical phenotype in human Phenotype in animal 
MTCO1 MELAS syndrome [93], myopathy [94], rhabdomyolysis [95], prostate cancer [96], myoglobinuria [97], motor neurone disease [98], exercise intolerance [99], epilepsy [100], acquired idiopathic sideroblastic anaemia [101], multisystem disorders [102], deafness, LHON or mitochondrial sensorineural hearing loss [103Mus musculus no overt phenotype [62
MTCO2 Encephalomyopathy [104], LHON [105], myopathy [106], hypertrophic cardiomyopathy [107], Alpers-Huttenlocher like disease [108], encephalomyopathy [109], pseudoexfoliation glaucoma [110], asthenozoospermy [111], rhabdomyolysis [112 
MTCO3 MIDD [113], LHON [99], myopathy [114], asthenozoospermia [115], Leigh disease [116], myoglobinuria [117], sporadic bilateral optic neuropathy [118], rhabdomyolysis [119], encephalopathy [120], progressive encephalopathy, MELAS or non-arteritic ischaemic optic neuropathy [121], hypertensive end-stage renal disease [122 
COX6B1 Severe infantile encephalomyopathy [23 
COX6A1 Recessive axonal or mixed form of Charcot-Marie-Tooth disease [24D. melanogaster, COX deficiency and premature death [58
COX7B Microphthalmia with linear skin lesions [25 
COX4I2, COX6A1COX6A2, COX7A1, COX7A2 Failure to thrive, psychomotor delay, progressive leucodystrophy, encephalomyopathy, epilepsy, hypotony, hepatopathy, anaemia, lactic acidosis and visual impairment [123C. elegans, knockdown of COX4 and COX5a homologues using RNA interference shortened lifespans [60]
Mus musculus COX4I2 KO lung pathology [63
COX6A2  Mus musculus KO led to cardiac dysfunction [65
COX7A1  Mus musculus; KO of the heart/skeletal muscle-specific COX7A1 exercise intolerance reminiscent of a mild myopathy [66] or dilated cardiomyopathy [67
COX7A2   
AIFM1 Encephalomyopathy [124], prenatal ventriculomegaly [125], hearing loss, external ophthalmoplegia, ataxia and muscle wasting [126], infantile motor neuron disease [127Mus musculus widespread AIFM1 loss of function results in CI deficiency with normal COX activity, leading to a variably severe phenotype hallmarked by progressive neurodegeneration, ataxia and blindness 
COA3 Neuropathy, exercise intolerance, obesity and short stature [128 
COA5 Cardiomyopathy [129 
COX10 Neonatal tubulopathy and encephalopathy, Leigh syndrome or cardiomyopathy [130,131Mus musculus transient liver KO caused increase in hepatocytes apoptosis [68], muscle-specific KO led to myopathy [69]; forebrain-specific Cox10 deletion resulted in astroglyosis and inflammation [70
COX15 Early-onset cardiomyopathy or Leigh syndrome [132,133 
FAM36A Ataxia and muscle hypotonia [134 
FARS2 Infantile-onset epilepsy [69 
FASTKD2 Encephalomyopathy in [135 
PET100 Infantile lactic acidosis [136]; Leigh syndrome [137 
SCO1 Neonatal-onset hepatic failure and encephalopathy [138 
SCO2 Neonatal cardioencephalomyopathy; myopia [36,139Mus musculus. A heterozygous KI/KO for SCO2 developed muscle weakness [71,72]
podocyte-specific KO of KLF6 (Krüppel-like factor 6) acting on SCO2-transcription increased focal segmental glomerulosclerosis induced by adryamicin [73
SURF1 Leigh syndrome [140]; villous atrophy and hypertrichosis, without central nervous system pathology [141D. melanogaster. Ubiquitous post-transcriptional silencing mostly larvae death some reaching pupal stage dying as early imagos [59]. Silencing in the central nervous system, cephalic low COX activity associated with behavioural and electrophysiological abnormality [59].
D. rerio. COX-reduced expression induced by using morpholinos, tissue-specific consequences with increased apoptosis in neural tissues but not in the heart that however showed time-increased poor performance [61] Mus musculus SURF1 KO did not manifest disease phenotype despite 30–40% decreased COX activity 
TACO1 Leigh syndrome [142 
Mutant gene Known clinical phenotype in human Phenotype in animal 
MTCO1 MELAS syndrome [93], myopathy [94], rhabdomyolysis [95], prostate cancer [96], myoglobinuria [97], motor neurone disease [98], exercise intolerance [99], epilepsy [100], acquired idiopathic sideroblastic anaemia [101], multisystem disorders [102], deafness, LHON or mitochondrial sensorineural hearing loss [103Mus musculus no overt phenotype [62
MTCO2 Encephalomyopathy [104], LHON [105], myopathy [106], hypertrophic cardiomyopathy [107], Alpers-Huttenlocher like disease [108], encephalomyopathy [109], pseudoexfoliation glaucoma [110], asthenozoospermy [111], rhabdomyolysis [112 
MTCO3 MIDD [113], LHON [99], myopathy [114], asthenozoospermia [115], Leigh disease [116], myoglobinuria [117], sporadic bilateral optic neuropathy [118], rhabdomyolysis [119], encephalopathy [120], progressive encephalopathy, MELAS or non-arteritic ischaemic optic neuropathy [121], hypertensive end-stage renal disease [122 
COX6B1 Severe infantile encephalomyopathy [23 
COX6A1 Recessive axonal or mixed form of Charcot-Marie-Tooth disease [24D. melanogaster, COX deficiency and premature death [58
COX7B Microphthalmia with linear skin lesions [25 
COX4I2, COX6A1COX6A2, COX7A1, COX7A2 Failure to thrive, psychomotor delay, progressive leucodystrophy, encephalomyopathy, epilepsy, hypotony, hepatopathy, anaemia, lactic acidosis and visual impairment [123C. elegans, knockdown of COX4 and COX5a homologues using RNA interference shortened lifespans [60]
Mus musculus COX4I2 KO lung pathology [63
COX6A2  Mus musculus KO led to cardiac dysfunction [65
COX7A1  Mus musculus; KO of the heart/skeletal muscle-specific COX7A1 exercise intolerance reminiscent of a mild myopathy [66] or dilated cardiomyopathy [67
COX7A2   
AIFM1 Encephalomyopathy [124], prenatal ventriculomegaly [125], hearing loss, external ophthalmoplegia, ataxia and muscle wasting [126], infantile motor neuron disease [127Mus musculus widespread AIFM1 loss of function results in CI deficiency with normal COX activity, leading to a variably severe phenotype hallmarked by progressive neurodegeneration, ataxia and blindness 
COA3 Neuropathy, exercise intolerance, obesity and short stature [128 
COA5 Cardiomyopathy [129 
COX10 Neonatal tubulopathy and encephalopathy, Leigh syndrome or cardiomyopathy [130,131Mus musculus transient liver KO caused increase in hepatocytes apoptosis [68], muscle-specific KO led to myopathy [69]; forebrain-specific Cox10 deletion resulted in astroglyosis and inflammation [70
COX15 Early-onset cardiomyopathy or Leigh syndrome [132,133 
FAM36A Ataxia and muscle hypotonia [134 
FARS2 Infantile-onset epilepsy [69 
FASTKD2 Encephalomyopathy in [135 
PET100 Infantile lactic acidosis [136]; Leigh syndrome [137 
SCO1 Neonatal-onset hepatic failure and encephalopathy [138 
SCO2 Neonatal cardioencephalomyopathy; myopia [36,139Mus musculus. A heterozygous KI/KO for SCO2 developed muscle weakness [71,72]
podocyte-specific KO of KLF6 (Krüppel-like factor 6) acting on SCO2-transcription increased focal segmental glomerulosclerosis induced by adryamicin [73
SURF1 Leigh syndrome [140]; villous atrophy and hypertrichosis, without central nervous system pathology [141D. melanogaster. Ubiquitous post-transcriptional silencing mostly larvae death some reaching pupal stage dying as early imagos [59]. Silencing in the central nervous system, cephalic low COX activity associated with behavioural and electrophysiological abnormality [59].
D. rerio. COX-reduced expression induced by using morpholinos, tissue-specific consequences with increased apoptosis in neural tissues but not in the heart that however showed time-increased poor performance [61] Mus musculus SURF1 KO did not manifest disease phenotype despite 30–40% decreased COX activity 
TACO1 Leigh syndrome [142 

Altogether, mutations in the three mtDNA encoded COX subunits can result in more than 20 different phenotypes. The degree of heteroplasmy (coexistence of variable levels of mutant and non-mutant mtDNA) in different tissues has been invoked to account for the large number of phenotypes associated with mutations in these mitochondrial genes. Although heteroplasmy may be a contributing factor, it cannot be the entire explanation as a similar clinical variability is observed in patients harbouring mutations in nuclear genes encoding RC components and assembly factors.

Mutations in nuclear COX genes

Relatively few mutations have been reported in nuclear genes encoding COX subunits and, prior to the discovery of the first mutation in COX6B1 [23], it was suggested that such mutations might be incompatible with life. A mutation in COX6B1 was associated with severe infantile encephalomyopathy, a quite typical presentation for a mitochondrial disease [23]. In a more recent study a mutation in COX6A1 was shown to cause a neurological disorder characterized by a recessive axonal or mixed form of Charcot-Marie-Tooth disease [24]. In addition, a mutation in COX7B was identified in a patient presenting microphthalmia with linear skin lesions, an unusual phenotype for a mitochondrial disease [25]. Loss-of-function mutations in nuclear-encoded subunits, although based on still limited data, appear to result in a loss of COX activity and accumulation of COX partially assembled complexes [26], however, the differences in clinical phenotype cannot be related to the function of a particular COX subunit or to its level of expression. A possible factor contributing to this phenomenon is the existence in human mitochondria of isoforms of some COX subunits with differential tissue-specific expression (Table 1 and Figure 4). COX6B1 like COX6A1 is ubiquitously expressed, whereas COX6B2 and COX6A2 are expressed mainly in testes and muscle tissue, respectively (Figure 4). Thus, isoform expression by itself may sometimes explain the phenotypic variability associated with mutations in these genes.

Mutant COX-assembly genes

Much more frequent mutations affecting COX occur in genes encoding protein factors involved in the biosynthesis and assembly of this enzyme (Figures 2 and 3, in red). Mutations in 15–20 genes, depending on whether they elicit a singular COX or a predominantly COX deficiency in patients, have been identified. Some of these genes products are factors known to act in pathways other than COX assembly (e.g. AIF1M or LRPPRC) [2733].

The temporally and perhaps spatially co-ordinated biogenesis of different RC complexes and their assembly into supercomplexes is likely to rely on factors that are not specific to a single RC complex. For example the product of OXA1, which was initially thought to be a specific COX factor [34], turned out to function as a more general inner membrane insertase of mitochondrial gene products. However, most COX factors that have been described, mainly from studies of Saccharomyces cerevisiae, and for which there are human homologues, have functions confined to COX biogenesis. With a few exceptions COX-assembly factors are ubiquitously expressed in humans and when mutated affect multiple organs. The SCO1 and SCO2 proteins are such exceptions as they display a tissue-specific pattern of expression that has been claimed to fit with the phenotype observed in patients with mutations in these proteins [35]. Even in this case, however, it is not always easy to correlate the presentation of the disease with tissue distribution of the protein. A case in point is the highly specific presentation as an autosomal-dominant high-grade myopia in patients with mutations in SCO2. This phenotype is difficult to reconcile with the restricted expression territory of the gene [36,37].

Mutations in COX-assembly factors, similar to those in the structural genes exhibit a multiplicity of phenotypes (see Table 2). A number of studies have concluded that COX activity is also critical for cell proliferation in lung, breast cancers, nasopharyngeal carcinomas and gliomas, perhaps by favouring metabolic reprograming required for cell proliferation [3842].

More than 20 phenotypes observed in patients with mutations in nuclear genes encoding COX subunits and assembly factors are not unlike those described for mutations in the mitochondrial genes. As already mentioned, the fact that these genes have a nuclear origin and are inherited by Mendelian laws excludes heteroplasmy as a contributing factor to the large diversity of phenotypes. Tissue-specific expression of some isoforms can also be discounted as there are numerous examples of gene products that have no isoforms yet also showing a range of different phenotypes.

A number of factors may contribute to the phenotypic variability. The function(s) of at least some proteins encoded by these nuclear genes is far from being completely understood and might be more diversified than presently recognized. Indeed, some of these genes products attributed to play a role in the assembly of COX could also functions in the biogenesis of other RC complexes. Mitochondria, depending on the organ and its energy needs [43,44], could be differently affected despite expressing a similar biochemical defect. Additionally, because mitochondria are intimately connected with and strongly influence other cellular activities [45], the capacity of organs and the whole organism to cope with mitochondrial dysfunction could depend on the mobilization of genetic resources, expected to be unique to each individual. Evidence is only beginning to emerge now showing that genetic background plays a crucial role in determining the consequence of mitochondrial dysfunctions [46,47].

STUDIES OF COX DEFICIENCY IN CULTURED CELLS, AND MICRO-ORGANISMS

Because of their low invasiveness, biopsies of skin fibroblasts or lymphocytes from patient blood samples have been (and still are) extensively used in studies of mitochondrial diseases [16]. They have been instrumental in clarifying questions related to the biochemistry of mitochondrial dysfunction and the levels of mtDNA heteroplasmy as a function of cell divisions [48,49]. Additionally, primary cell cultures have proved to be useful to establish the deleterious character of a number of COX gene mutations, especially exploiting their requirement for glucose in culture media. These cells have been particularly useful in devising rational pharmacological [50] and genetic [51] approaches to fight the consequences of COX deficiencies. Exciting recent studies offer the promise that COX deficiencies in patients might one day be ameliorated by an AOX (alternative oxidase) by-pass. Human COX-defective fibroblasts unable to grow in the absence of glucose as a result of COX15 silencing were rescued by ectopic expression of AOX from Ciona intestinalis [52]. This non-proton motive oxidase restores NADH and succinate oxidation in mitochondria without increasing their ATP generating capacity (Figure 1A). The rescue of COX-defective fibroblasts by AOX suggests that the deleterious effect of the COX deficiency in these cells and under the culture conditions used is not the result of lowered ATP production. This is also supported by recent data showing AOX rescue of the different phenotypes seen in COX deficient fruit flies [53].

A number of important questions about COX deficiency remain unanswered, and, for obvious reasons they cannot be solved by studies of cultured cells. Foremost are tissue specificity and development-related phenotypes. In view of this shortcoming several COX-defective models have been created to unravel COX subunit/isoform function, hopefully to model human mitochondrial diseases, and ideally to find ways to counteract disease-causing mutations.

Most of our basic understanding of COX and its assembly comes from studies of microorganisms, particularly of the unicellular yeast, S. cerevisiae. In addition to the large arsenal of genetic tools for manipulating the mitochondrial and nuclear genes of this organism, it is also extremely useful in validating the pathogenic impact of a particular mutation identified in a constituent of the RC [54]. A requirement for such heterologous complementation tests is the presence of a yeast homologue for a mutated human gene. Although this is usually the case with genes coding for RC complexes II, III and IV, importantly human complex I has no homologue in S. cerevisiae, which uses instead two different dehydrogenases completely unrelated to human complex I. The absence of complex I in S. cerevisiae mitochondria implies a different organization of the respirasome that could also influence the deficit related phenotype. There are also important differences in the genetic systems of mammalian and yeast mitochondria. The absence of introns in mammalian mtDNA, and the existence of different sets of translational activators and regulatory proteins than those present in yeast implies that the balanced output of nuclear and mitochondrial gene products of COX and other complexes of the RC must be attained by regulatory mechanisms different from those described in yeast [5557]. Obviously, yeast is also not the best system to study questions related to tissue specificity and the effects on developmental parameters of COX and RC deficiencies.

HIGHER ORGANISMS TO STUDY COX DEFICIENCY

Several groups have exploited the fruit fly (Drosophila melanogaster), the worm (Caenorhabditis elegans), the Zebrafish (Danio rerio) or the mouse as models for genetic modification of COX-related genes to evaluate their consequent phenotypes in a higher organism. Interestingly, the phenotypes observed in these model organisms have not always been consistent with those of human patients. A mutation in COX6A of Drosophila caused a COX deficiency and premature death, whereas different mutations in the human gene, similarly causing COX deficiency, result in encephalomyopathy [58]. Body-wide post-transcriptional silencing of the fly homologue of the COX-assembly gene SURF1 caused extensive larvae death as early as the imago stage of pupal development [59]. Flies with SURF1 silenced in the central nervous system only, reached adulthood with low cephalic COX activity and with behavioural and electrophysiological abnormality [59]. Knockdown of the COX4 and COX5A homologues using RNA interference shortened the lifespan of worms. Surprisingly, the authors reported that the COX defect was accompanied by a loss of complex I function [60]. Reduced expression of either COX5A or SURF1 induced with morpholinos in Zebra fish elicited a panoply of tissue-specific abnormalities, including increased apoptosis in neural tissues but not in the heart. Heart function, however, decreased with time [61].

Several genes for COX subunits have also been targeted in the mouse. No obvious phenotype could be linked to a mild COX1 point mutant, a missense mutation at nt 6589 (T6589C) converting a highly conserved valine at codon 421 to alanine (V421A) [62]. A KO (knockout) of the nuclear COX4I2, however, caused a lung pathology, stressing the importance of the gene product for normal lung function [63]. In humans, a mutation in COX4I2 causes exocrine pancreatic insufficiency, dyserythropoeitic anaemia, and calvarial hyperostosis [64] affecting organs/tissues supposedly not expressing this protein, which might suggest an indirect effect of the mutation. A KO of COX6A2 led to cardiac dysfunction [65] and a KO of the heart/skeletal muscle-specific COX7A1 to exercise intolerance reminiscent of a mild myopathy [66] or dilated cardiomyopathy [67]. Known assembly factors for COX have also been inactivated in the mouse. A transient liver KO of COX10 induced hepatocytes apoptosis [68] and a muscle-specific KO of COX10 led to myopathy [69]. A forebrain-specific COX10 deletion resulted in astrogliosis and inflammation [70]. A SURF1 KO did not manifest a disease phenotype despite 30–40% decreased COX activity, suggesting that the mitochondrial concentration of this enzyme is higher than required to sustain cell growth and survival. Heterozygous mice with SCO2 KI/KO developed muscle weakness [71,72], whereas podocyte-specific KO of KLF6 (Krüppel-like factor 6) acting on SCO2 transcription, increased focal segmental glomerulosclerosis induced by adryamicin [73]. A heterozygous KO of CHCHD4 exhibited a COX deficiency and reduced weight gain [28].

Genetic manipulation of the model organisms produce in general rather well defined phenotypes. This contrasts sharply with the large variation in phenotypes frequently observed in patients with mutations in the homologous genes. This discrepancy can be explained to some extent by the use of clonally selected animals and by organ-specific targeting [46]. The major impact of genetic background in the phenotypic expression of an RC dysfunction can also account for the variability [74]. This is clearly demonstrated by the large number of phenotypes observed in a genetically heterogeneous Harlequin mouse population harbouring a proviral insertion that reduces expression of the AIF1M gene by 80% [75], resulting only in a significant complex I deficiency [27,74].

THERAPEUTIC HOPES

Since our last review on COX, more than 10 years ago [76], very few approaches have demonstrated efficacy in counteracting COX deficiency in patients. Yet in a small number of cases [77,78], without human intervention and mostly for unknown reason, a partial reversal of the disease has been seen. This gives hope that reversing disease phenotype owing to an efficient therapy is not out of reach. This particularly holds true when considering mtDNA mutations where partial change of mutant load might be sufficient to counteract at least disease progression. This has been shown possibly reachable in cultured human cells by using mitochondria-targeted nuclases (mitoTALEN) specifically identifying mutant mtDNA [79]. Furthermore, thanks to the rapid progress being made in gene vectorization, gene therapy for a number of human diseases including COX deficiency has become an attainable goal. Accordingly, gene therapy has shown some promise in alleviating Leber Hereditary Optic Neuropathy (LHON), which was established to be in part related to a COX deficiency [80]. In a mouse model of LHON stemming from a mutation in the mitochondrial ND4 gene, reversal of the disease was observed by optimizing the allotopic expression in the nucleus of an adeno-associated virusharbouring a version of ND4 modified for mitochondrial import and translation [8183]. LHON disease is particularly suitable for this approach as the retinal ganglion cell layer, which as a consequence of its degeneration is instrumental in the loss of vision, can be easily accessed. Gene therapy as a means of treating patients with LHON is still in the early stage with trials being done in France and the US. Unfortunately, this approach is hampered by problems of accessibility for most COX-related disorders affecting other organs or tissues.

Approaches alternative to gene therapy have also been explored to fight COX deficiency and other RC defects [84]. A ketogenic diet has been claimed to increase energy metabolism in the brain by enhancing mitochondrial biogenesis, which in turn raises the cellular concentrations of adenosine and ATP, enhances neuron–glia interactions and may even shift the level of heteroplasmy [84]. Numerous studies in which mixture(s) of non-toxic dietary supplements (creatine, lipoic acid, CoQ10, etc.) have been tested in patients, claimed to ameliorate some symptoms. Definitive evidence of their efficacy, however, is lacking. On the other hand, treating the symptoms such as strokes with arginine in MELAS patients with a COX defect may help [85]. Some drugs should however be avoided. For example, valproate, but possibly other antiepileptic drugs as well, have been shown to trigger hepatic failure in COX-defective patients [86,87]. Because of a lack of evidences for increased oxidative stress in COX impaired cells [88,89], the use of antioxidants is also unlikely to be effective for COX deficient patients.

The pan-PPAR agonist bezafibrate has been shown to rescue RC deficiency in COX-defective human cells [50,90] and in COX-defective mouse [69]. However, this effect of bezafibrate could not be reproduced in a SURF KO, a SCO2 KO/KI, and in a muscle-restricted mouse with a COX15 KO. On the other hand, treatment of these three COX-defective mice with the AMPK agonist AICAR led to a partial recovery of COX [91]. At this time it is important that these observations be corroborated by additional experiments and hopefully confirmed in patients.

CONCLUSION

Much progress has been made in our understanding of the molecular basis for COX deficiencies in patients, thereby reducing diagnostic wavering and allowing the clinician to better inform family members. The numerous mutations in structural and assembly genes identified in COX deficient patients has also served as an incentive to better understand their functions. Research along this line has revealed that in some cases genes products involved in COX biogenesis also play a more general role in maintaining the respiratory integrity of mitochondria by participating in the assembly pathways for other RC complexes. These studies have contributed to the significant progress made in recent years in deciphering mechanisms responsible for the biogenesis of the RC complexes and the role of the factors involved in this process.

The same cannot be said of the efforts to find ways of slowing down the course of these often devastating diseases. The emergence of gene therapy gives hope that development of vectors allowing targeting of a specific organ will be paralleled by equal strides in the treatment of diseases including those stemming from mitochondrial disorders.

We thank the Association Française contre les Maladies Mitochondriales (AMMI), the Association Française contre l'Ataxie de Friedreich (AFAF), the Association Française contre les Myopathies (AFM) and l'association Ouvrir Les Yeux (OLY) for their support.

FUNDING

This work was supported by the Agence Nationale de la Recherche [grant numbers ANR-08-GENO-0029, ANR-09-EBIO-0020, ANR-11-BSV1-0017, ANR-12-BSV1-0010 (to P.R. and M.C.D.)]; and the National Institutes of Health [grant number GM1118640 (to A.T.)].

Abbreviations

     
  • COX

    cytochrome c oxidase

  •  
  • KO

    knockout

  •  
  • MITRAC

    mitochondrial translation regulation assembly intermediate of cytochrome c oxidase

  •  
  • mtDNA

    mitochondrial DNA

  •  
  • RC

    respiratory chain TIM, translocase of the inner membrane

  •  
  • TOM

    translocase of the outer membrane

References

References
1
Pierron
D.
Wildman
D.E.
Huttemann
M.
Markondapatnaikuni
G.C.
Aras
S.
Grossman
L.I.
Cytochrome c oxidase: evolution of control via nuclear subunit addition
Biochim. Biophys. Acta
2012
, vol. 
1817
 (pg. 
590
-
597
)
[PubMed]
2
Kadenbach
B.
Huttemann
M.
The subunit composition and function of mammalian cytochrome c oxidase
Mitochondrion
2015
, vol. 
24
 (pg. 
64
-
76
)
[PubMed]
3
Schagger
H.
Pfeiffer
K.
Supercomplexes in the respiratory chains of yeast and mammalian mitochondria
EMBO J.
2000
, vol. 
19
 (pg. 
1777
-
1783
)
[PubMed]
4
Schagger
H.
de Coo
R.
Bauer
M.F.
Hofmann
S.
Godinot
C.
Brandt
U.
Significance of respirasomes for the assembly/stability of human respiratory chain complex I
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
36349
-
36353
)
[PubMed]
5
Gutman
M.
Electron flux through the mitochondrial ubiquinone
Biochim. Biophys. Acta
1980
, vol. 
594
 (pg. 
53
-
84
)
[PubMed]
6
Rustin
P.
Moreau
F.
Lance
C.
Malate oxidation in plant mitochondria via malic enzyme and the cyanide-insensitive electron transport pathway
Plant Physiol.
1980
, vol. 
66
 (pg. 
457
-
462
)
[PubMed]
7
Diaz
F.
Fukui
H.
Garcia
S.
Moraes
C.T.
Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts
Mol. Cell Biol.
2006
, vol. 
26
 (pg. 
4872
-
4881
)
[PubMed]
8
Saada
A.
Edvardson
S.
Shaag
A.
Chung
W.K.
Segel
R.
Miller
C.
Jalas
C.
Elpeleg
O.
Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7
J. Inherit. Metab. Dis.
2011
, vol. 
35
 (pg. 
125
-
131
)
9
Bonne
G.
Seibel
P.
Possekel
S.
Marsac
C.
Kadenbach
B.
Expression of human cytochrome c oxidase subunits during fetal development
Eur. J. Biochem.
1993
, vol. 
217
 (pg. 
1099
-
1107
)
[PubMed]
10
Huttemann
M.
Lee
I.
Grossman
L.I.
Doan
J.W.
Sanderson
T.H.
Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease
Adv. Exp. Med. Biol.
2012
, vol. 
748
 (pg. 
237
-
264
)
[PubMed]
11
Musatov
A.
Robinson
N.C.
Bound cardiolipin is essential for cytochrome c oxidase proton translocation
Biochimie
2014
, vol. 
105
 (pg. 
159
-
164
)
[PubMed]
12
Yoshikawa
S.
Muramoto
K.
Shinzawa-Itoh
K.
Mochizuki
M.
Structural studies on bovine heart cytochrome c oxidase
Biochim. Biophys. Acta
2012
, vol. 
1817
 (pg. 
579
-
589
)
[PubMed]
13
Balsa
E.
Marco
R.
Perales-Clemente
E.
Szklarczyk
R.
Calvo
E.
Landazuri
M.O.
Enriquez
J.A.
NDUFA4 is a subunit of complex IV of the mammalian electron transport chain
Cell Metab.
2012
, vol. 
16
 (pg. 
378
-
386
)
[PubMed]
14
Pitceathly
R.D.
Rahman
S.
Wedatilake
Y.
Polke
J.M.
Cirak
S.
Foley
A.R.
Sailer
A.
Hurles
M.E.
Stalker
J.
Hargreaves
I.
, et al. 
NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease
Cell Rep.
2013
, vol. 
3
 (pg. 
1795
-
1805
)
[PubMed]
15
MITOMAP
A Human Mitochondrial Genome Database
2007
 
16
Rustin
P.
Chretien
D.
Bourgeron
T.
Gerard
B.
Rotig
A.
Saudubray
J.M.
Munnich
A.
Biochemical and molecular investigations in respiratory chain deficiencies
Clin. Chim. Acta
1994
, vol. 
228
 (pg. 
35
-
51
)
[PubMed]
17
Rustin
P.
Chretien
D.
Bourgeron
T.
Wucher
A.
Saudubray
J.M.
Rotig
A.
Munnich
A.
Assessment of the mitochondrial respiratory chain
Lancet
1991
, vol. 
338
 pg. 
60
 
[PubMed]
18
DiMauro
S.
Tanji
K.
Schon
E.A.
The many clinical faces of cytochrome c oxidase deficiency
Adv. Exp. Med. Biol.
2012
, vol. 
748
 (pg. 
341
-
357
)
[PubMed]
19
Alfadhel
M.
Lillquist
Y.P.
Waters
P.J.
Sinclair
G.
Struys
E.
McFadden
D.
Hendson
G.
Hyams
L.
Shoffner
J.
Vallance
H.D.
Infantile cardioencephalopathy due to a COX15 gene defect: report and review
Am. J. Med. Genet. A.
2011
, vol. 
155A
 (pg. 
840
-
844
)
[PubMed]
20
Chadha
R.
Shah
R.
Mani
S.
Analysis of reported SCO2 gene mutations affecting cytochrome c oxidase activity in various diseases
Bioinformation
2014
, vol. 
10
 (pg. 
329
-
333
)
[PubMed]
21
Hamblet
N.S.
Ragland
B.
Ali
M.
Conyers
B.
Castora
F.J.
Mutations in mitochondrial-encoded cytochrome c oxidase subunits I, II, and III genes detected in Alzheimer's disease using single-strand conformation polymorphism
Electrophoresis
2006
, vol. 
27
 (pg. 
398
-
408
)
[PubMed]
22
Ng
L.F.
Gruber
J.
Cheah
I.K.
Goo
C.K.
Cheong
W.F.
Shui
G.
Sit
K.P.
Wenk
M.R.
Halliwell
B.
The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease
Free Radic. Biol. Med.
2014
, vol. 
71
 (pg. 
390
-
401
)
[PubMed]
23
Massa
V.
Fernandez-Vizarra
E.
Alshahwan
S.
Bakhsh
E.
Goffrini
P.
Ferrero
I.
Mereghetti
P.
D'Adamo
P.
Gasparini
P.
Zeviani
M.
Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase
Am. J. Hum. Genet.
2008
, vol. 
82
 (pg. 
1281
-
1289
)
[PubMed]
24
Tamiya
G.
Makino
S.
Hayashi
M.
Abe
A.
Numakura
C.
Ueki
M.
Tanaka
A.
Ito
C.
Toshimori
K.
Ogawa
N.
, et al. 
A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease
Am. J. Hum. Genet.
2014
, vol. 
95
 (pg. 
294
-
300
)
[PubMed]
25
Indrieri
A.
van Rahden
V.A.
Tiranti
V.
Morleo
M.
Iaconis
D.
Tammaro
R.
D'Amato
I.
Conte
I.
Maystadt
I.
Demuth
S.
, et al. 
Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease
Am. J. Hum. Genet.
2012
, vol. 
91
 (pg. 
942
-
949
)
[PubMed]
26
Fornuskova
D.
Stiburek
L.
Wenchich
L.
Vinsova
K.
Hansikova
H.
Zeman
J.
Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b
Biochem. J.
2010
, vol. 
428
 (pg. 
363
-
3674
)
[PubMed]
27
Vahsen
N.
Cande
C.
Briere
J.J.
Benit
P.
Joza
N.
Larochette
N.
Mastroberardino
P.G.
Pequignot
M.O.
Casares
N.
Lazar
V.
, et al. 
AIF deficiency compromises oxidative phosphorylation
EMBO. J.
2004
, vol. 
23
 (pg. 
4679
-
4689
)
[PubMed]
28
Hangen
E.
Feraud
O.
Lachkar
S.
Mou
H.
Doti
N.
Fimia
G.M.
Lam
N.V.
Zhu
C.
Godin
I.
Muller
K.
, et al. 
Interaction between AIF and CHCHD4 regulates respiratory chain biogenesis
Mol. Cell.
2015
, vol. 
58
 (pg. 
1001
-
1014
)
[PubMed]
29
Ruzzenente
B.
Metodiev
M.D.
Wredenberg
A.
Bratic
A.
Park
C.B.
Camara
Y.
Milenkovic
D.
Zickermann
V.
Wibom
R.
Hultenby
K.
, et al. 
LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs
EMBO J.
2012
, vol. 
31
 (pg. 
443
-
456
)
[PubMed]
30
Meyer
K.
Buettner
S.
Ghezzi
D.
Zeviani
M.
Bano
D.
Nicotera
P.
Loss of apoptosis-inducing factor critically affects MIA40 function
Cell Death Dis.
2015
, vol. 
6
 pg. 
e1814
 
[PubMed]
31
Xu
F.
Morin
C.
Mitchell
G.
Ackerley
C.
Robinson
B.H.
The role of the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome c oxidase) I and COX III mRNA
Biochem. J.
2004
, vol. 
382
 
Pt 1
(pg. 
331
-
336
)
[PubMed]
32
Sasarman
F.
Nishimura
T.
Antonicka
H.
Weraarpachai
W.
Shoubridge
E.A.
Tissue-specific responses to the LRPPRC founder mutation in French Canadian Leigh Syndrome
Hum. Mol. Genet.
2015
, vol. 
24
 (pg. 
480
-
491
)
[PubMed]
33
Mourier
A.
Ruzzenente
B.
Brandt
T.
Kuhlbrandt
W.
Larsson
N.G.
Loss of LRPPRC causes ATP synthase deficiency
Hum. Mol. Genet.
2014
, vol. 
23
 (pg. 
2580
-
2592
)
[PubMed]
34
Bonnefoy
N.
Chalvet
F.
Hamel
P.
Slonimski
P.P.
Dujardin
G.
OXA1, a Saccharomyces cerevisiae nuclear gene whose sequence is conserved from prokaryotes to eukaryotes controls cytochrome oxidase biogenesis
J. Mol. Biol.
1994
, vol. 
239
 (pg. 
201
-
212
)
[PubMed]
35
Brosel
S.
Yang
H.
Tanji
K.
Bonilla
E.
Schon
E.A.
Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease
Am. J. Pathol.
2010
, vol. 
177
 (pg. 
2541
-
2548
)
[PubMed]
36
Tran-Viet
K.N.
Powell
C.
Barathi
V.A.
Klemm
T.
Maurer-Stroh
S.
Limviphuvadh
V.
Soler
V.
Ho
C.
Yanovitch
T.
Schneider
G.
, et al. 
Mutations in SCO2 are associated with autosomal-dominant high-grade myopia
Am. J. Hum. Genet.
2013
, vol. 
92
 (pg. 
820
-
826
)
[PubMed]
37
Jiang
D.
Li
J.
Xiao
X.
Li
S.
Jia
X.
Sun
W.
Guo
X.
Zhang
Q.
Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing
Invest. Ophthalmol. Vis. Sci.
2015
, vol. 
56
 (pg. 
339
-
345
)
38
Guo
Q.
Zhang
H.
Zhang
L.
He
Y.
Weng
S.
Dong
Z.
Wang
J.
Zhang
P.
Nao
R.
MicroRNA-21 regulates non-small cell lung cancer cell proliferation by affecting cell apoptosis via COX-19
Int. J. Clin. Exp. Med.
2015
, vol. 
8
 (pg. 
8835
-
8841
)
[PubMed]
39
Liu
F.
Zhang
W.
You
X.
Liu
Y.
Li
Y.
Wang
Z.
Wang
Y.
Zhang
X.
Ye
L.
The oncoprotein HBXIP promotes glucose metabolism reprogramming via downregulating SCO2 and PDHA1 in breast cancer
Oncotarget.
2015
, vol. 
6
 (pg. 
27199
-
27213
)
40
Srinivasan
S.
Guha
M.
Dong
D.W.
Whelan
K.A.
Ruthel
G.
Uchikado
Y.
Natsugoe
S.
Nakagawa
H.
Avadhani
N.G.
Disruption of cytochrome c oxidase function induces the Warburg effect and metabolic reprogramming
Oncogene
2015
 
2015 Jul 6. doi:10.1038/onc.2015.227. [Epub ahead of print]
41
Oliva
C.R.
Markert
T.
Gillespie
G.Y.
Griguer
C.E.
Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas
Oncotarget.
2015
, vol. 
6
 (pg. 
4330
-
4344
)
[PubMed]
42
Shen
Y.A.
Wang
C.Y.
Hsieh
Y.T.
Chen
Y.J.
Wei
Y.H.
Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma
Cell Cycle
2015
, vol. 
14
 (pg. 
86
-
98
)
[PubMed]
43
Mazat
J.P.
Rossignol
R.
Malgat
M.
Rocher
C.
Faustin
B.
Letellier
T.
What do mitochondrial diseases teach us about normal mitochondrial functions…that we already knew: threshold expression of mitochondrial defects
Biochim. Biophys. Acta
2001
, vol. 
1504
 (pg. 
20
-
30
)
[PubMed]
44
Gusdon
A.M.
Fernandez-Bueno
G.A.
Wohlgemuth
S.
Fernandez
J.
Chen
J.
Mathews
C.E.
Respiration and substrate transport rates as well as reactive oxygen species production distinguish mitochondria from brain and liver
BMC Biochem.
2015
, vol. 
16
 pg. 
22
 
[PubMed]
45
Turnbull
D.M.
Rustin
P.
Genetic and biochemical intricacy shapes mitochondrial cytopathies
Neurobiol. Dis.
2015
 
2015 Feb 12. pii: S0969-9961(15)00023-6. doi: 10.1016/j.nbd.2015.02.003. [Epub ahead of print]
46
Benit
P.
El-Khoury
R.
Schiff
M.
Sainsard-Chanet
A.
Rustin
P.
Genetic background influences mitochondrial function: modeling mitochondrial disease for therapeutic development
Trends Mol. Med.
2010
, vol. 
16
 (pg. 
210
-
217
)
[PubMed]
47
Gil Borlado
M.C.
Moreno Lastres
D.
Gonzalez Hoyuela
M.
Moran
M.
Blazquez
A.
Pello
R.
Marin Buera
L.
Gabaldon
T.
Garcia Penas
J.J.
Martin
M.A.
, et al. 
Impact of the mitochondrial genetic background in complex III deficiency
PLoS One.
2010
, vol. 
5
 
9
pg. 
e12801
 
48
King
M.P.
Attardi
G.
Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation
Science
1989
, vol. 
246
 (pg. 
500
-
503
)
[PubMed]
49
Bourgeron
T.
Chretien
D.
Rotig
A.
Munnich
A.
Rustin
P.
Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures
J. Biol. Chem.
1993
, vol. 
268
 (pg. 
19369
-
19376
)
[PubMed]
50
Bastin
J.
Aubey
F.
Rotig
A.
Munnich
A.
Djouadi
F.
Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients' cells lacking its components
J. Clin. Endocrinol. Metab.
2008
, vol. 
93
 (pg. 
1433
-
1441
)
[PubMed]
51
Rustin
P.
Jacobs
H.T.
Respiratory chain alternative enzymes as tools to better understand and counteract respiratory chain deficiencies in human cells and animals
Physiol. Plant.
2009
, vol. 
137
 (pg. 
362
-
370
)
[PubMed]
52
Dassa
E.P.
Dufour
E.
Goncalves
S.
Paupe
V.
Hakkaart
G.A.
Jacobs
H.T.
Rustin
P.
Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells
EMBO Mol. Med.
2009
, vol. 
1
 (pg. 
30
-
36
)
[PubMed]
53
Kemppainen
K.K.
Rinne
J.
Sriram
A.
Lakanmaa
M.
Zeb
A.
Tuomela
T.
Popplestone
A.
Singh
S.
Sanz
A.
Rustin
P.
, et al. 
Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
Hum. Mol. Genet.
2014
, vol. 
23
 (pg. 
2078
-
2093
)
[PubMed]
54
Gaignard
P.
Menezes
M.
Schiff
M.
Bayot
A.
Rak
M.
Ogier de Baulny
H.
Su
C.H.
Gilleron
M.
Lombes
A.
Abida
H.
, et al. 
Mutations in CYC1, encoding cytochrome c1 subunit of respiratory chain complex III, cause insulin-responsive hyperglycemia
Am. J. Hum. Genet.
2013
, vol. 
93
 (pg. 
384
-
389
)
[PubMed]
55
Barrientos
A.
Zambrano
A.
Tzagoloff
A.
Mss51p and Cox14p jointly regulate mitochondrial Cox1p expression in Saccharomyces cerevisiae
EMBO J.
2004
, vol. 
23
 (pg. 
3472
-
3482
)
[PubMed]
56
Pierrel
F.
Khalimonchuk
O.
Cobine
P.A.
Bestwick
M.
Winge
D.R.
Coa2 is an assembly factor for yeast cytochrome c oxidase biogenesis that facilitates the maturation of Cox1
Mol. Cell Biol.
2008
, vol. 
28
 (pg. 
4927
-
4939
)
[PubMed]
57
Mick
D.U.
Fox
T.D.
Rehling
P.
Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation
Nat. Rev. Mol. Cell Biol.
2011
, vol. 
12
 (pg. 
14
-
20
)
[PubMed]
58
Liu
W.
Gnanasambandam
R.
Benjamin
J.
Kaur
G.
Getman
P.B.
Siegel
A.J.
Shortridge
R.D.
Singh
S.
Mutations in cytochrome c oxidase subunit VIa cause neurodegeneration and motor dysfunction in Drosophila
Genetics
2007
, vol. 
176
 (pg. 
937
-
946
)
[PubMed]
59
Zordan
M.A.
Cisotto
P.
Benna
C.
Agostino
A.
Rizzo
G.
Piccin
A.
Pegoraro
M.
Sandrelli
F.
Perini
G.
Tognon
G.
, et al. 
Post-transcriptional silencing and functional characterization of the Drosophila melanogaster homolog of human Surf1
Genetics
2006
, vol. 
172
 (pg. 
229
-
241
)
[PubMed]
60
Suthammarak
W.
Yang
Y.Y.
Morgan
P.G.
Sedensky
M.M.
Complex I function is defective in complex IV-deficient Caenorhabditis elegans
J. Biol. Chem.
2009
, vol. 
284
 (pg. 
6425
-
6435
)
[PubMed]
61
Baden
K.N.
Murray
J.
Capaldi
R.A.
Guillemin
K.
Early developmental pathology due to cytochrome c oxidase deficiency is revealed by a new zebrafish model
J. Biol. Chem.
2007
, vol. 
282
 (pg. 
34839
-
34849
)
[PubMed]
62
Fan
W.
Waymire
K.G.
Narula
N.
Li
P.
Rocher
C.
Coskun
P.E.
Vannan
M.A.
Narula
J.
Macgregor
G.R.
Wallace
D.C.
A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations
Science
2008
, vol. 
319
 (pg. 
958
-
962
)
[PubMed]
63
Huttemann
M.
Lee
I.
Gao
X.
Pecina
P.
Pecinova
A.
Liu
J.
Aras
S.
Sommer
N.
Sanderson
T.H.
Tost
M.
, et al. 
Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology
FASEB J.
2012
, vol. 
26
 (pg. 
3916
-
3930
)
[PubMed]
64
Shteyer
E.
Saada
A.
Shaag
A.
Al-Hijawi
F.A.
Kidess
R.
Revel-Vilk
S.
Elpeleg
O.
Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene
Am. J. Hum. Genet.
2009
, vol. 
84
 (pg. 
412
-
417
)
[PubMed]
65
Radford
N.B.
Wan
B.
Richman
A.
Szczepaniak
L.S.
Li
J.L.
Li
K.
Pfeiffer
K.
Schagger
H.
Garry
D.J.
Moreadith
R.W.
Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH
Am. J. Physiol. Heart Circ. Physiol.
2002
, vol. 
282
 (pg. 
H726
-
H733
)
[PubMed]
66
Lee
I.
Huttemann
M.
Liu
J.
Grossman
L.I.
Malek
M.H.
Deletion of heart-type cytochrome c oxidase subunit 7a1 impairs skeletal muscle angiogenesis and oxidative phosphorylation
J. Physiol.
2012
, vol. 
590
 
Pt 20
(pg. 
5231
-
5243
)
[PubMed]
67
Huttemann
M.
Klewer
S.
Lee
I.
Pecinova
A.
Pecina
P.
Liu
J.
Lee
M.
Doan
J.W.
Larson
D.
Slack
E.
, et al. 
Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy
Mitochondrion
2012
, vol. 
12
 (pg. 
294
-
304
)
[PubMed]
68
Diaz
F.
Garcia
S.
Hernandez
D.
Regev
A.
Rebelo
A.
Oca-Cossio
J.
Moraes
C.T.
Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies
Gut.
2008
, vol. 
57
 (pg. 
232
-
242
)
[PubMed]
69
Diaz
F.
Thomas
C.K.
Garcia
S.
Hernandez
D.
Moraes
C.T.
Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency
Hum. Mol. Genet.
2005
, vol. 
14
 (pg. 
2737
-
2748
)
[PubMed]
70
Noe
N.
Dillon
L.
Lellek
V.
Diaz
F.
Hida
A.
Moraes
C.T.
Wenz
T.
Bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy
Mitochondrion
2013
, vol. 
13
 (pg. 
417
-
426
)
[PubMed]
71
Yang
H.
Brosel
S.
Acin-Perez
R.
Slavkovich
V.
Nishino
I.
Khan
R.
Goldberg
I.J.
Graziano
J.
Manfredi
G.
Schon
E.A.
Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2
Hum. Mol. Genet.
2010
, vol. 
19
 (pg. 
170
-
180
)
[PubMed]
72
Acin-Perez
R.
Salazar
E.
Brosel
S.
Yang
H.
Schon
E.A.
Manfredi
G.
Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects
EMBO Mol. Med.
2009
, vol. 
1
 (pg. 
392
-
406
)
[PubMed]
73
Mallipattu
S.K.
Horne
S.J.
D'Agati
V.
Narla
G.
Liu
R.
Frohman
M.A.
Dickman
K.
Chen
E.Y.
Ma'ayan
A.
Bialkowska
A.B.
, et al. 
Kruppel-like factor 6 regulates mitochondrial function in the kidney
J. Clin. Invest.
2015
, vol. 
125
 (pg. 
1347
-
1361
)
[PubMed]
74
Bénit
P.
Goncalves
S.
Dassa
E.P.
Brière
J.J.
Rustin
P.
The variability of the Harlequin mouse phenotype resembles that of human mitochondrial-complex I-deficiency syndromes
PLoS One
2008
, vol. 
3
 pg. 
e3208
 
[PubMed]
75
Klein
J.A.
Longo-Guess
C.M.
Rossmann
M.P.
Seburn
K.L.
Hurd
R.E.
Frankel
W.N.
Bronson
R.T.
Ackerman
S.L.
The harlequin mouse mutation downregulates apoptosis-inducing factor
Nature
2002
, vol. 
419
 (pg. 
367
-
374
)
[PubMed]
76
Barrientos
A.
Barros
M.H.
Valnot
I.
Rotig
A.
Rustin
P.
Tzagoloff
A.
Cytochrome oxidase in health and disease
Gene
2002
, vol. 
286
 (pg. 
53
-
63
)
[PubMed]
77
Goldenberg
P.C.
Steiner
R.D.
Merkens
L.S.
Dunaway
T.
Egan
R.A.
Zimmerman
E.A.
Nesbit
G.
Robinson
B.
Kennaway
N.G.
Remarkable improvement in adult Leigh syndrome with partial cytochrome c oxidase deficiency
Neurology
2003
, vol. 
60
 (pg. 
865
-
868
)
[PubMed]
78
Uusimaa
J.
Jungbluth
H.
Fratter
C.
Crisponi
G.
Feng
L.
Zeviani
M.
Hughes
I.
Treacy
E.P.
Birks
J.
Brown
G.K.
, et al. 
Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease
J. Med. Genet.
2011
, vol. 
48
 (pg. 
660
-
668
)
[PubMed]
79
Bacman
S.R.
Williams
S.L.
Pinto
M.
Peralta
S.
Moraes
C.T.
Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs
Nat. Med.
2013
, vol. 
19
 (pg. 
1111
-
1113
)
[PubMed]
80
Meyerson
C.
Van Stavern
G.
McClelland
C.
Leber hereditary optic neuropathy: current perspectives
Clin. Ophthalmol.
2015
, vol. 
9
 (pg. 
1165
-
1176
)
[PubMed]
81
Ellouze
S.
Augustin
S.
Bouaita
A.
Bonnet
C.
Simonutti
M.
Forster
V.
Picaud
S.
Sahel
J.A.
Corral-Debrinski
M.
Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction
Am. J. Hum. Genet.
2008
, vol. 
83
 (pg. 
373
-
387
)
82
Cwerman-Thibault
H.
Augustin
S.
Lechauve
C.
Ayache
J.
Ellouze
S.
Sahel
J.A.
Corral-Debrinski
M.
Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss
Mol. Ther. Methods Clin. Dev.
2015
, vol. 
2
 pg. 
15003
 
[PubMed]
83
Koilkonda
R.D.
Yu
H.
Chou
T.H.
Feuer
W.J.
Ruggeri
M.
Porciatti
V.
Tse
D.
Hauswirth
W.W.
Chiodo
V.
Boye
S.L.
, et al. 
Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial
JAMA Ophthalmol.
2014
, vol. 
132
 (pg. 
409
-
420
)
[PubMed]
84
Dimauro
S.
Rustin
P.
A critical approach to the therapy of mitochondrial respiratory chain and oxidative phosphorylation diseases
Biochim. Biophys. Acta
2008
, vol. 
1792
 (pg. 
1159
-
1167
)
[PubMed]
85
El-Hattab
A.W.
Adesina
A.M.
Jones
J.
Scaglia
F.
MELAS syndrome: clinical manifestations, pathogenesis, and treatment options
Mol. Genet. Metab.
2015
, vol. 
116
 (pg. 
4
-
12
)
86
Chabrol
B.
Mancini
J.
Chretien
D.
Rustin
P.
Munnich
A.
Pinsard
N.
Valproate-induced hepatic failure in a case of cytochrome c oxidase deficiency
Eur. J. Pediatr.
1994
, vol. 
153
 (pg. 
133
-
135
)
[PubMed]
87
Berger
I.
Segal
I.
Shmueli
D.
Saada
A.
The effect of antiepileptic drugs on mitochondrial activity: a pilot study
J. Child Neurol.
2010
, vol. 
25
 (pg. 
541
-
545
)
[PubMed]
88
Geromel
V.
Kadhom
N.
Cebalos-Picot
I.
Ouari
O.
Polidori
A.
Munnich
A.
Rotig
A.
Rustin
P.
Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA
Hum. Mol. Genet.
2001
, vol. 
10
 (pg. 
1221
-
1228
)
[PubMed]
89
Diaz
F.
Garcia
S.
Padgett
K.R.
Moraes
C.T.
A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions
Hum. Mol. Genet.
2012
, vol. 
21
 (pg. 
5066
-
5077
)
[PubMed]
90
Casarin
A.
Giorgi
G.
Pertegato
V.
Siviero
R.
Cerqua
C.
Doimo
M.
Basso
G.
Sacconi
S.
Cassina
M.
Rizzuto
R.
, et al. 
Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations
Orphanet. J. Rare Dis.
2012
, vol. 
7
 pg. 
21
 
[PubMed]
91
Viscomi
C.
Bottani
E.
Civiletto
G.
Cerutti
R.
Moggio
M.
Fagiolari
G.
Schon
E.A.
Lamperti
C.
Zeviani
M.
In vivo correction of COX deficiency by activation of the AMPK/PGC-1alpha axis
Cell Metab.
2011
, vol. 
14
 (pg. 
80
-
90
)
[PubMed]
92
Gray
K.A.
Daugherty
L.C.
Gordon
S.M.
Seal
R.L.
Wright
M.W.
Bruford
E.A.
Genenames.org: the HGNC resources in 2013
Nucleic Acids Res.
2013
, vol. 
41
 (pg. 
D545
-
D552
)
[PubMed]
93
Lamperti
C.
Diodato
D.
Lamantea
E.
Carrara
F.
Ghezzi
D.
Mereghetti
P.
Rizzi
R.
Zeviani
M.
MELAS-like encephalomyopathy caused by a new pathogenic mutation in the mitochondrial DNA encoded cytochrome c oxidase subunit I
Neuromuscul. Disord.
2012
, vol. 
22
 (pg. 
990
-
994
)
[PubMed]
94
Valente
L.
Piga
D.
Lamantea
E.
Carrara
F.
Uziel
G.
Cudia
P.
Zani
A.
Farina
L.
Morandi
L.
Mora
M.
, et al. 
Identification of novel mutations in five patients with mitochondrial encephalomyopathy
Biochim. Biophys. Acta
2009
, vol. 
1787
 (pg. 
491
-
501
)
[PubMed]
95
Kollberg
G.
Moslemi
A.R.
Lindberg
C.
Holme
E.
Oldfors
A.
Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I
J. Neuropathol. Exp. Neurol.
2005
, vol. 
64
 (pg. 
123
-
128
)
[PubMed]
96
Petros
J.A.
Baumann
A.K.
Ruiz-Pesini
E.
Amin
M.B.
Sun
C.Q.
Hall
J.
Lim
S.
Issa
M.M.
Flanders
W.D.
Hosseini
S.H.
, et al. 
mtDNA mutations increase tumorigenicity in prostate cancer
Proc. Natl. Acad. Sci. U.S.A.
2005
, vol. 
102
 (pg. 
719
-
724
)
[PubMed]
97
Karadimas
C.L.
Greenstein
P.
Sue
C.M.
Joseph
J.T.
Tanji
K.
Haller
R.G.
Taivassalo
T.
Davidson
M.M.
Shanske
S.
Bonilla
E.
, et al. 
Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA
Neurology
2000
, vol. 
55
 (pg. 
644
-
649
)
[PubMed]
98
Comi
G.P.
Bordoni
A.
Salani
S.
Franceschina
L.
Sciacco
M.
Prelle
A.
Fortunato
F.
Zeviani
M.
Napoli
L.
Bresolin
N.
, et al. 
Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease
Ann. Neurol.
1998
, vol. 
43
 (pg. 
110
-
116
)
[PubMed]
99
Pereira
L.
Soares
P.
Radivojac
P.
Li
B.
Samuels
D.C.
Comparing phylogeny and the predicted pathogenicity of protein variations reveals equal purifying selection across the global human mtDNA diversity
Am. J. Hum. Genet.
2011
, vol. 
88
 (pg. 
433
-
439
)
[PubMed]
100
Varlamov
D.A.
Kudin
A.P.
Vielhaber
S.
Schroder
R.
Sassen
R.
Becker
A.
Kunz
D.
Haug
K.
Rebstock
J.
Heils
A.
, et al. 
Metabolic consequences of a novel missense mutation of the mtDNA CO I gene
Hum. Mol. Genet.
2002
, vol. 
11
 (pg. 
1797
-
1805
)
[PubMed]
101
Gattermann
N.
Retzlaff
S.
Wang
Y.L.
Hofhaus
G.
Heinisch
J.
Aul
C.
Schneider
W.
Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia
Blood
1997
, vol. 
90
 (pg. 
4961
-
4972
)
[PubMed]
102
D'Aurelio
M.
Pallotti
F.
Barrientos
A.
Gajewski
C.D.
Kwong
J.Q.
Bruno
C.
Beal
M.F.
Manfredi
G.
In vivo regulation of oxidative phosphorylation in cells harboring a stop-codon mutation in mitochondrial DNA-encoded cytochrome c oxidase subunit I
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
46925
-
46932
)
[PubMed]
103
Nishigaki
Y.
Ueno
H.
Coku
J.
Koga
Y.
Fujii
T.
Sahashi
K.
Nakano
K.
Yoneda
M.
Nonaka
M.
Tang
L.
, et al. 
Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations
Mitochondrion
2010
, vol. 
10
 (pg. 
300
-
308
)
[PubMed]
104
Clark
K.M.
Taylor
R.W.
Johnson
M.A.
Chinnery
P.F.
Chrzanowska-Lightowlers
Z.M.
Andrews
R.M.
Nelson
I.P.
Wood
N.W.
Lamont
P.J.
Hanna
M.G.
, et al. 
An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy
Am. J. Hum. Genet.
1999
, vol. 
64
 (pg. 
1330
-
1339
)
[PubMed]
105
Abu-Amero
K.K.
Bosley
T.M.
Mitochondrial abnormalities in patients with LHON-like optic neuropathies
Invest. Ophthalmol. Vis. Sci.
2006
, vol. 
47
 (pg. 
4211
-
4220
)
[PubMed]
106
Rahman
S.
Taanman
J.W.
Cooper
J.M.
Nelson
I.
Hargreaves
I.
Meunier
B.
Hanna
M.G.
Garcia
J.J.
Capaldi
R.A.
Lake
B.D.
, et al. 
A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy
Am. J. Hum. Genet.
1999
, vol. 
65
 (pg. 
1030
-
1039
)
[PubMed]
107
Wei
Y.L.
Yu
C.A.
Yang
P.
Li
A.L.
Wen
J.Y.
Zhao
S.M.
Liu
H.X.
Ke
Y.N.
Campbell
W.
Zhang
Y.G.
, et al. 
Novel mitochondrial DNA mutations associated with Chinese familial hypertrophic cardiomyopathy
Clin. Exp. Pharmacol. Physiol.
2009
, vol. 
36
 (pg. 
933
-
939
)
[PubMed]
108
Uusimaa
J.
Finnila
S.
Vainionpaa
L.
Karppa
M.
Herva
R.
Rantala
H.
Hassinen
I.E.
Majamaa
K.
A mutation in mitochondrial DNA-encoded cytochrome c oxidase II gene in a child with Alpers-Huttenlocher-like disease
Pediatrics
2003
, vol. 
111
 (pg. 
e262
-
e268
)
[PubMed]
109
Horvath
R.
Schoser
B.G.
Muller-Hocker
J.
Volpel
M.
Jaksch
M.
Lochmuller
H.
Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy
Neuromuscul. Disord.
2005
, vol. 
15
 (pg. 
851
-
857
)
[PubMed]
110
Abu-Amero
K.K.
Bosley
T.M.
Morales
J.
Analysis of nuclear and mitochondrial genes in patients with pseudoexfoliation glaucoma
Mol. Vis.
2008
, vol. 
14
 (pg. 
29
-
36
)
[PubMed]
111
Siwar
B.G.
Myriam
G.
Afif
B.M.
Emna
M.R.
Nozha
C.
Afifa
S.
Faiza
F.
Leila
A.K.
Two novel mutations in COII and tRNA(His) mitochondrial genes in asthenozoospermic infertiles men
Biochem. Biophys. Res. Commun.
2014
, vol. 
450
 (pg. 
610
-
615
)
[PubMed]
112
McFarland
R.
Taylor
R.W.
Chinnery
P.F.
Howell
N.
Turnbull
D.M.
A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis
Neuromuscul. Disord.
2004
, vol. 
14
 (pg. 
162
-
166
)
[PubMed]
113
Tabebi
M.
Mkaouar-Rebai
E.
Mnif
M.
Kallabi
F.
Ben Mahmoud
A.
Ben Saad
W.
Charfi
N.
Keskes-Ammar
L.
Kamoun
H.
Abid
M.
, et al. 
A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy
Biochem. Biophys. Res. Commun.
2015
, vol. 
459
 (pg. 
353
-
360
)
[PubMed]
114
Horvath
R.
Scharfe
C.
Hoeltzenbein
M.
Do
B.H.
Schroder
C.
Warzok
R.
Vogelgesang
S.
Lochmuller
H.
Muller-Hocker
J.
Gerbitz
K.D.
, et al. 
Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene
J. Med. Genet.
2002
, vol. 
39
 (pg. 
812
-
816
)
[PubMed]
115
Baklouti-Gargouri
S.
Ghorbel
M.
Ben Mahmoud
A.
Mkaouar-Rebai
E.
Cherif
M.
Chakroun
N.
Sellami
A.
Fakhfakh
F.
Ammar-Keskes
L.
Mitochondrial DNA mutations and polymorphisms in asthenospermic infertile men
Mol. Biol. Rep.
2013
, vol. 
40
 (pg. 
4705
-
4712
)
[PubMed]
116
Mkaouar-Rebai
E.
Ellouze
E.
Chamkha
I.
Kammoun
F.
Triki
C.
Fakhfakh
F.
Molecular-clinical correlation in a family with a novel heteroplasmic Leigh syndrome missense mutation in the mitochondrial cytochrome c oxidase III gene
J. Child Neurol.
2011
, vol. 
26
 (pg. 
12
-
20
)
[PubMed]
117
Figueroa-Martinez
F.
Vazquez-Acevedo
M.
Cortes-Hernandez
P.
Garcia-Trejo
J.J.
Davidson
E.
King
M.P.
Gonzalez-Halphen
D.
What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes
Mitochondrion
2011
, vol. 
11
 (pg. 
147
-
154
)
[PubMed]
118
Bosley
T.M.
Brodsky
M.C.
Glasier
C.M.
Abu-Amero
K.K.
Sporadic bilateral optic neuropathy in children: the role of mitochondrial abnormalities
Invest. Ophthalmol. Vis. Sci.
2008
, vol. 
49
 (pg. 
5250
-
5256
)
[PubMed]
119
Marotta
R.
Chin
J.
Kirby
D.M.
Chiotis
M.
Cook
M.
Collins
S.J.
Novel single base pair COX III subunit deletion of mitochondrial DNA associated with rhabdomyolysis
J. Clin. Neurosci.
2011
, vol. 
18
 (pg. 
290
-
292
)
[PubMed]
120
Hanna
M.G.
Nelson
I.P.
Rahman
S.
Lane
R.J.
Land
J.
Heales
S.
Cooper
M.J.
Schapira
A.H.
Morgan-Hughes
J.A.
Wood
N.W.
Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA
Am. J. Hum. Genet.
1998
, vol. 
63
 (pg. 
29
-
36
)
[PubMed]
121
Lenaz
G.
Baracca
A.
Carelli
V.
D'Aurelio
M.
Sgarbi
G.
Solaini
G.
Bioenergetics of mitochondrial diseases associated with mtDNA mutations
Biochim. Biophys. Acta
2004
, vol. 
1658
 (pg. 
89
-
94
)
[PubMed]
122
Levin
L.
Zhidkov
I.
Gurman
Y.
Hawlena
H.
Mishmar
D.
Functional recurrent mutations in the human mitochondrial phylogeny: dual roles in evolution and disease
Genome Biol. Evol.
2013
, vol. 
5
 (pg. 
876
-
890
)
[PubMed]
123
Vondrackova
A.
Vesela
K.
Hansikova
H.
Docekalova
D.Z.
Rozsypalova
E.
Zeman
J.
Tesarova
M.
High-resolution melting analysis of 15 genes in 60 patients with cytochrome-c oxidase deficiency
J. Hum. Genet.
2012
, vol. 
57
 (pg. 
442
-
448
)
[PubMed]
124
Ghezzi
D.
Sevrioukova
I.
Invernizzi
F.
Lamperti
C.
Mora
M.
D'Adamo
P.
Novara
F.
Zuffardi
O.
Uziel
G.
Zeviani
M.
Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor
Am. J. Hum. Genet.
2010
, vol. 
86
 (pg. 
639
-
649
)
[PubMed]
125
Berger
I.
Ben-Neriah
Z.
Dor-Wolman
T.
Shaag
A.
Saada
A.
Zenvirt
S.
Raas-Rothschild
A.
Nadjari
M.
Kaestner
K.H.
Elpeleg
O.
Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing
Mol. Genet. Metab.
2011
, vol. 
104
 (pg. 
517
-
520
)
[PubMed]
126
Kettwig
M.
Schubach
M.
Zimmermann
F.A.
Klinge
L.
Mayr
J.A.
Biskup
S.
Sperl
W.
Gartner
J.
Huppke
P.
From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1
Mitochondrion
2015
, vol. 
21
 (pg. 
12
-
18
)
[PubMed]
127
Diodato
D.
Tasca
G.
Verrigni
D.
D'Amico
A.
Rizza
T.
Tozzi
G.
Martinelli
D.
Verardo
M.
Invernizzi
F.
Nasca
A.
, et al. 
A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease
Eur. J. Hum. Genet.
2015
 
2015 Jul 15. doi: 10.1038/ejhg.2015.141. [Epub ahead of print]
128
Ostergaard
E.
Weraarpachai
W.
Ravn
K.
Born
A.P.
Jonson
L.
Duno
M.
Wibrand
F.
Shoubridge
E.A.
Vissing
J.
Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature
J. Med. Genet.
2015
, vol. 
52
 (pg. 
203
-
207
)
[PubMed]
129
Huigsloot
M.
Nijtmans
L.G.
Szklarczyk
R.
Baars
M.J.
van den Brand
M.A.
Hendriksfranssen
M.G.
van den Heuvel
L.P.
Smeitink
J.A.
Huynen
M.A.
Rodenburg
R.J.
A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy
Am. J. Hum. Genet.
2011
, vol. 
88
 (pg. 
488
-
493
)
[PubMed]
130
Valnot
I.
von Kleist-Retzow
J.C.
Barrientos
A.
Gorbatyuk
M.
Taanman
J.W.
Mehaye
B.
Rustin
P.
Tzagoloff
A.
Munnich
A.
Rotig
A.
A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency
Hum. Mol. Genet.
2000
, vol. 
9
 (pg. 
1245
-
1249
)
[PubMed]
131
Antonicka
H.
Leary
S.C.
Guercin
G.H.
Agar
J.N.
Horvath
R.
Kennaway
N.G.
Harding
C.O.
Jaksch
M.
Shoubridge
E.A.
Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency
Hum. Mol. Genet.
2003
, vol. 
12
 (pg. 
2693
-
26702
)
[PubMed]
132
Antonicka
H.
Mattman
A.
Carlson
C.G.
Glerum
D.M.
Hoffbuhr
K.C.
Leary
S.C.
Kennaway
N.G.
Shoubridge
E.A.
Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy
Am. J. Hum. Genet.
2003
, vol. 
72
 (pg. 
101
-
114
)
[PubMed]
133
Oquendo
C.E.
Antonicka
H.
Shoubridge
E.A.
Reardon
W.
Brown
G.K.
Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome
J. Med. Genet.
2004
, vol. 
41
 (pg. 
540
-
544
)
[PubMed]
134
Szklarczyk
R.
Wanschers
B.F.
Nijtmans
L.G.
Rodenburg
R.J.
Zschocke
J.
Dikow
N.
van den Brand
M.A.
Hendriks-Franssen
M.G.
Gilissen
C.
Veltman
J.A.
, et al. 
A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia
Hum. Mol. Genet.
2013
, vol. 
22
 (pg. 
656
-
667
)
[PubMed]
135
Ghezzi
D.
Saada
A.
D'Adamo
P.
Fernandez-Vizarra
E.
Gasparini
P.
Tiranti
V.
Elpeleg
O.
Zeviani
M.
FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency
Am. J. Hum. Genet.
2008
, vol. 
83
 (pg. 
415
-
423
)
[PubMed]
136
Olahova
M.
Haack
T.B.
Alston
C.L.
Houghton
J.A.
He
L.
Morris
A.A.
Brown
G.K.
McFarland
R.
Chrzanowska-Lightowlers
Z.M.
Lightowlers
R.N.
, et al. 
A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency
Eur. J. Hum. Genet.
2015
, vol. 
23
 (pg. 
935
-
939
)
[PubMed]
137
Lim
S.C.
Smith
K.R.
Stroud
D.A.
Compton
A.G.
Tucker
E.J.
Dasvarma
A.
Gandolfo
L.C.
Marum
J.E.
McKenzie
M.
Peters
H.L.
, et al. 
A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome
Am. J. Hum. Genet.
2014
, vol. 
94
 (pg. 
209
-
222
)
[PubMed]
138
Valnot
I.
Osmond
S.
Gigarel
N.
Mehaye
B.
Amiel
J.
Cormier-Daire
V.
Munnich
A.
Bonnefont
J.P.
Rustin
P.
Rotig
A.
Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy
Am. J. Hum. Genet.
2000
, vol. 
67
 (pg. 
1104
-
1109
)
[PubMed]
139
Papadopoulou
L.C.
Sue
C.M.
Davidson
M.M.
Tanji
K.
Nishino
I.
Sadlock
J.E.
Krishna
S.
Walker
W.
Selby
J.
Glerum
D.M.
, et al. 
Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene
Nat. Genet.
1999
, vol. 
23
 (pg. 
333
-
337
)
[PubMed]
140
Tiranti
V.
Hoertnagel
K.
Carrozzo
R.
Galimberti
C.
Munaro
M.
Granatiero
M.
Zelante
L.
Gasparini
P.
Marzella
R.
Rocchi
M.
, et al. 
Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency
Am. J. Hum. Genet.
1998
, vol. 
63
 (pg. 
1609
-
1621
)
[PubMed]
141
Von Kleist-Retzow
J.C.
Yao
J.
Taanman
J.W.
Chantrel
K.
Chretien
D.
Cormier-Daire
V.
Rotig
A.
Munnich
A.
Rustin
P.
Shoubridge
E.A.
Mutations in SURF1 are not specifically associated with Leigh syndrome
J. Med. Genet.
2001
, vol. 
38
 (pg. 
109
-
113
)
[PubMed]
142
Weraarpachai
W.
Antonicka
H.
Sasarman
F.
Seeger
J.
Schrank
B.
Kolesar
J.E.
Lochmuller
H.
Chevrette
M.
Kaufman
B.A.
Horvath
R.
, et al. 
Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome
Nat. Genet.
2009
, vol. 
41
 (pg. 
833
-
837
)
[PubMed]
143
Orr
A.L.
Ashok
D.
Sarantos
M.R.
Ng
R.
Shi
T.
Gerencser
A.A.
Hughes
R.E.
Brand
M.D.
Novel inhibitors of mitochondrial sn-glycerol 3-phosphate dehydrogenase
PLoS One
2014
, vol. 
9
 pg. 
e89938
 
[PubMed]
144
Rehling
P.
Brandner
K.
Pfanner
N.
Mitochondrial import and the twin-pore translocase
Nat. Rev. Mol. Cell Biol.
2004
, vol. 
5
 (pg. 
519
-
530
)
[PubMed]
145
Mick
D.U.
Dennerlein
S.
Wiese
H.
Reinhold
R.
Pacheu-Grau
D.
Lorenzi
I.
Sasarman
F.
Weraarpachai
W.
Shoubridge
E.A.
Warscheid
B.
, et al. 
MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation
Cell
2012
, vol. 
151
 (pg. 
1528
-
1541
)
[PubMed]
146
Dennerlein
S.
Oeljeklaus
S.
Jans
D.
Hellwig
C.
Bareth
B.
Jakobs
S.
Deckers
M.
Warscheid
B.
Rehling
P.
MITRAC7 acts as a COX1-specific chaperone and reveals a checkpoint during cytochrome c oxidase assembly
Cell Rep.
2015
, vol. 
12
 (pg. 
1644
-
1655
)
[PubMed]