Mitochondrial complex I has a molecular mass of almost 1 MDa and comprises more than 40 polypeptides. Fourteen central subunits harbour the bioenergetic core functions. We are only beginning to understand the significance of the numerous accessory subunits. The present review addresses the role of accessory subunits for assembly, stability and regulation of complex I and for cellular functions not directly associated with redox-linked proton translocation.

Overview

Proton-translocating NADH:ubiquinone oxidoreductase (respiratory complex I) is a very large and complex membrane protein [1]. Fourteen central subunits represent the minimal form of the enzyme and are conserved from bacteria to humans. In complex I from the aerobic yeast Yarrowia lipolytica 28 accessory subunits with a total mass of more than 421 kDa were detected accounting for 44% of the mass of the holoenzyme [2,3]. In bovine complex I, the presence of 30 accessory subunits [4,5] is well established and orthologues have been predicted or detected in human complex I [6,7]. The functional significance of accessory subunits is highlighted by an increasing number of reports on complex I dysfunction connected with this group of subunits [8]. The present review focuses on accessory complex I subunits from human and bovine complex I and from the yeast genetic model Y. lipolytica. These three systems lack a uniform nomenclature and we will indicate all three subunit names throughout (Bt, Hs and Yl subscripts indicate Bos taurus, Homo sapiens and Yarrowia lipolytica respectively; compare Table 1).

Table 1
Accessory subunits of mitochondrial complex I
Y. lipolytica* (kDa) Human† Bovine‡ (kDa) Remarks Associated disease(s) 
Matrix arm (N-module and Q-module)     
 NUEM (40.4) NDUFA9 39-kDa (39.1) NADPH-binding short-chain dehydrogenase; active–deactive transition Leigh syndrome [75
 NUZM (19.8) NDUFA7 B14.5a (12.6) Phosphorylation  
 N7BM (16.2) NDUFA12 B17.2 (17.1) Related to assembly factor N7BML (NDUFAF2) Leigh syndrome [76
 NUYM (15.9) NDUFS4 AQDQ§ (15.3) Phosphorylation Leigh(-like) syndrome [8,73,74
 NUFM (15.6) NDUFA5 B13 (13.2) Active–deactive transition Autism [77,78
 NB4M (14.6) NDUFA6 B14 (15.0) LYR protein LYRM6 nitration; see Angerer [14aDown-regulated in HIV infection [79
 NUMM (13.1) NDUFS6 13-kDa (10.5) Putative Zn2+-binding site PDB codes of bacterial homologues: 2JVM, 2JRR, 2JZ8 Fatal neonatal acidaemia [23,80
 ACPM1 (9.6) – – Acyl carrier protein, compare PDB code 2DNW  
 NI8M (9.5) NDUFA2 B8 (11.0) PDB code 1S3A Leigh syndrome [81
 – NDUFV3 10-kDa (8.4)   
PP-module     
 NUPM (19.2) NDUFA8 PGIV (20.0) Quadruple CX9 
 NUXM (18.6) – – MTMD  
 NB6M (14.0) NDUFA13 B16.6 (16.6) STMD; phosphorylation; in humans and cows identical with GRIM-19, regulation of cell death Target of viral RNA [50] and proteins [48,49], tumorigenesis [42,82,83
 NIMM (9.7) NDUFA1 MWFE (8.1) STMD; phosphorylation; assembly Leigh-like syndrome, neurodegeneration [8486
 NI9M (9.0) NDUFA3 B9 (9.3) STMD  
 NEBM (7.9) – – STMD  
PD-module     
 NESM∥ (23.4) NDUFB11 ESSS (14.5) STMD; phosphorylation; neuronal differentiation, see [87 
 NUJM (20.7) NDUFA11 B14.7 (14.8)¶ MTMD, related to TIM 17,22, 23, see [88]; dual location in plant, see [89Infantile lactic acidaemia, encephalocardiomyopathy [90
 NIAM (14.6) NDUFB8 ASHI (18.7) STMD; nitration  
 NUNM (13.3)  STMD   
 NI2M (12.9) NDUFB9 B22 (21.7) LYR protein LYRM3; see Angerer [14aMuscular hypotonia and raised blood lactate level [91
 NB8M (11.1) NDUFB7 B18 (16.5) Double CX9C; myristoylated, see [92 
 NIDM (10.9) NDUFB10 PDSW (20.8) Phosphorylation  
 NB5M (10.5) NDUFB4 B15 (15.1) STMD, nitration  
 ACPM2 (10.1) – – Acyl carrier protein; compare PDB code 2DNW  
 NIPM (9.9) NDUFS5 PFFD, 15-kDa (12.5) Double CX9 
 NUUM (9.7) – – STMD  
 NB2M (6.8) NDUFB13 B12 (11.n)** STMD; methylated, see [92 
 – NDUFB5 SGDH (16.7) STMD††  
 – NDUFB6 B17 (15.5) STMD††  
 – NDUFC2 B14.5b (14.1)†† MTMD††; phosphorylation  
 – NDUFB2 AGGG (8.5) STMD††  
 – NDUFB1 MNLL (7.0) MTMD††  
Localization unclear     
 ST1 (34.6) – – Sulfur transferase  
 – NDUFA10 42 kDa (36.7) Iα subcomplex phosphorylation Leigh syndrome [93
 – NDUFAB1 SDAP (10.7) Acyl carrier protein, compare PDB code 2DNW  
 – NDUFC1 KFYI (5.8)   
Y. lipolytica* (kDa) Human† Bovine‡ (kDa) Remarks Associated disease(s) 
Matrix arm (N-module and Q-module)     
 NUEM (40.4) NDUFA9 39-kDa (39.1) NADPH-binding short-chain dehydrogenase; active–deactive transition Leigh syndrome [75
 NUZM (19.8) NDUFA7 B14.5a (12.6) Phosphorylation  
 N7BM (16.2) NDUFA12 B17.2 (17.1) Related to assembly factor N7BML (NDUFAF2) Leigh syndrome [76
 NUYM (15.9) NDUFS4 AQDQ§ (15.3) Phosphorylation Leigh(-like) syndrome [8,73,74
 NUFM (15.6) NDUFA5 B13 (13.2) Active–deactive transition Autism [77,78
 NB4M (14.6) NDUFA6 B14 (15.0) LYR protein LYRM6 nitration; see Angerer [14aDown-regulated in HIV infection [79
 NUMM (13.1) NDUFS6 13-kDa (10.5) Putative Zn2+-binding site PDB codes of bacterial homologues: 2JVM, 2JRR, 2JZ8 Fatal neonatal acidaemia [23,80
 ACPM1 (9.6) – – Acyl carrier protein, compare PDB code 2DNW  
 NI8M (9.5) NDUFA2 B8 (11.0) PDB code 1S3A Leigh syndrome [81
 – NDUFV3 10-kDa (8.4)   
PP-module     
 NUPM (19.2) NDUFA8 PGIV (20.0) Quadruple CX9 
 NUXM (18.6) – – MTMD  
 NB6M (14.0) NDUFA13 B16.6 (16.6) STMD; phosphorylation; in humans and cows identical with GRIM-19, regulation of cell death Target of viral RNA [50] and proteins [48,49], tumorigenesis [42,82,83
 NIMM (9.7) NDUFA1 MWFE (8.1) STMD; phosphorylation; assembly Leigh-like syndrome, neurodegeneration [8486
 NI9M (9.0) NDUFA3 B9 (9.3) STMD  
 NEBM (7.9) – – STMD  
PD-module     
 NESM∥ (23.4) NDUFB11 ESSS (14.5) STMD; phosphorylation; neuronal differentiation, see [87 
 NUJM (20.7) NDUFA11 B14.7 (14.8)¶ MTMD, related to TIM 17,22, 23, see [88]; dual location in plant, see [89Infantile lactic acidaemia, encephalocardiomyopathy [90
 NIAM (14.6) NDUFB8 ASHI (18.7) STMD; nitration  
 NUNM (13.3)  STMD   
 NI2M (12.9) NDUFB9 B22 (21.7) LYR protein LYRM3; see Angerer [14aMuscular hypotonia and raised blood lactate level [91
 NB8M (11.1) NDUFB7 B18 (16.5) Double CX9C; myristoylated, see [92 
 NIDM (10.9) NDUFB10 PDSW (20.8) Phosphorylation  
 NB5M (10.5) NDUFB4 B15 (15.1) STMD, nitration  
 ACPM2 (10.1) – – Acyl carrier protein; compare PDB code 2DNW  
 NIPM (9.9) NDUFS5 PFFD, 15-kDa (12.5) Double CX9 
 NUUM (9.7) – – STMD  
 NB2M (6.8) NDUFB13 B12 (11.n)** STMD; methylated, see [92 
 – NDUFB5 SGDH (16.7) STMD††  
 – NDUFB6 B17 (15.5) STMD††  
 – NDUFC2 B14.5b (14.1)†† MTMD††; phosphorylation  
 – NDUFB2 AGGG (8.5) STMD††  
 – NDUFB1 MNLL (7.0) MTMD††  
Localization unclear     
 ST1 (34.6) – – Sulfur transferase  
 – NDUFA10 42 kDa (36.7) Iα subcomplex phosphorylation Leigh syndrome [93
 – NDUFAB1 SDAP (10.7) Acyl carrier protein, compare PDB code 2DNW  
 – NDUFC1 KFYI (5.8)   

*Position and molecular masses of mature proteins according to [3].

†Molecular masses of mature proteins according to [18].

‡Subunit composition according to [6] and as reviewed in [7].

§Designation 18 kDa subunit is used frequently instead.

∥Initial designation NUWM.

¶Not determined; calculated mass in parentheses.

**Two masses reported.

††Topology prediction for human complex I using HMMTOP [94].

Topology, structure and relationship with other proteins

The architecture of the complete eukaryotic enzyme complex has been characterized by X-ray crystallography [9] and electron microscopy [10,11] (Figure 1). The matrix arm of complex I harbours the NADH oxidation and the ubiquinone reduction module (N-module and Q-module respectively). The membrane arm comprises a proximal and a distal proton pump module (PP-module and PD-module, respectively). Structural information on individual accessory subunits is still very limited. High-resolution structures were determined by NMR spectroscopy for NDUFA2Hs (NI8MYl/B8Bt) [12] and alphaproteobacterial homologues [13] of subunit NUMMYl/NDUFS6Hs/13-kDaBt expressed in Escherichia coli (Northeast Structural Genomics Project), and, using a cell-free expression system (Riken Structural Genomics Project), for the acyl carrier domain of the human ACPM (mitochondrial acyl carrier protein) that was detected as subunit NDUFAB1Hs in human complex I [6]. Subunit NUEMYl/NDUFA9Hs/39-kDaBt belongs to the structurally well-characterized short-chain dehydrogenase family and comprises an NADPH-binding site [14]. Subunits NB4MYl/B14Bt/NDUFA6Hs and NI2MYl/B22Bt/NDUFB9Hs are members of the LYR (leucine/tyrosine/arginine) protein family extensively discussed in the review by Angerer [14a] in this issue of Biochemical Society Transactions.

A topological model for the arrangement of subunits in complex I has been derived from proteomic analysis of different subcomplexes and sequence-based targeting predictions [3]. Accessory complex I subunits can be divided into three different groups: (i) hydrophilic subunits of the matrix arm, (ii) membrane arm subunits with single or multiple transmembrane domains, STMD [15] and MTMD respectively, and (iii) subunits associated with the membrane arm but without transmembrane domains (Table 1). In the latter group, subunits can be exposed to either the matrix or the intermembrane space side. Subunits NB8MYl/NDUFB7Hs/B18Bt, NIPMYl/NDUFS5Hs/PFFDBt and NUPMYl/NDUFA8Hs/PGIVBt contain a conserved pattern of cysteine residues (double CX9C; in the case of NUPMYl/NDUFA8Hs/PGIVBt, quadruple CX9C) that is a hallmark of polypeptides imported to the intermembrane space by the Mia40 import system (reviewed in [16]); structural models for all three subunits have been calculated [17] and the electron-density maps of Y. lipolytica complex I show an extensive layer of mostly helical protein mass on the intermembrane space side of the membrane arm [9]. Mammalian complex I subunits PDSWBt/NDUFB10Hs and B22Bt/NDUFB9Hs each comprise two pairs of cysteine residues. However, unorthodox CXnC intervals question processing by the Mia40 import machinery.

Architecture of mitochondrial complex I

Figure 1
Architecture of mitochondrial complex I

The matrix arm comprises the N-module (yellow) and the Q-module (orange). Iron–sulfur clusters (blue spheres) transfer electrons from the initial acceptor FMN to the ubiquinone reduction site (Q/QH2, ubiquinone in oxidized and reduced form). The membrane arm is divided into a PP-module and a PD-module respectively.

Figure 1
Architecture of mitochondrial complex I

The matrix arm comprises the N-module (yellow) and the Q-module (orange). Iron–sulfur clusters (blue spheres) transfer electrons from the initial acceptor FMN to the ubiquinone reduction site (Q/QH2, ubiquinone in oxidized and reduced form). The membrane arm is divided into a PP-module and a PD-module respectively.

Recent evidence suggests that the matrix arm of Y. lipolytica complex I comprises nine hydrophilic accessory subunits, presumably including NB4MYl (B14Bt/NDUFA6Hs) and the acyl carrier protein subunit ACPM1Yl ([3], and H. Angerer, M. Radermacher, M. Mańkowska, M. Steger, K. Zwicker, H. Heide, U. Brandt and V. Zickermann, unpublished work) (Table 1). Despite overall consistency in subunit composition the following differences to the matrix arm of complex I from the mammalian enzyme should be noted. The mammalian 10-kDa subunit (NDUFV3Hs) that is known to be associated with the flavoprotein fragment harbouring the NADH oxidation site [18] is not present in Y. lipolytica complex I. The position of the acyl carrier protein subunit SDAPBt/NDUFA1Hs in mammalian complex I is ambiguous because it was found in different subcomplexes of the enzyme. The Y. lipoytica NUEM subunit was detected in a matrix arm fragment, but the orthologous bovine 39-kDa subunit is absent from the corresponding bovine subcomplex Iλ. As this may rather reflect a different fragmentation behaviour, there is no compelling evidence to assume a difference in subunit position between complex I from the two organisms. The PP-module of Y. lipolytica complex I contains four STMD subunits and one MTMD subunit. Only three of these five membrane-intrinsic subunits are found in the mammalian enzymes; the position of subunit NUPMYl (NDUFA8Hs/PGIVBt) at the ‘heel’ of complex I was demonstrated by electron microscopy [3]. The PD-module contains six STMD subunits, one MTMD subunit and five hydrophilic polypeptides in Y. lipolytica complex I. Several more membrane-intrinsic subunits have been assigned to the corresponding Iβ subcomplex of bovine complex I [18] (Table 1). The position of subunit NESMYl (ESSSBt/NDUFB11Hs) was determined by electron microscopy [19]. The PD-module of Y. lipolytica contains a second ACPM, ACPM2. This position is in agreement with the presence of bovine subunit SDAP in subcomplex Iβ [18], but at variance with its concomitant detection in subcomplex Iα that includes the matrix arm. Moreover, it is impossible to conclude unambiguously from sequence alignments whether the bovine subunit is more similar to Y. lipolytica ACPM1 or ACPM2 (results not shown).

Function

Complex I assembly and stability

Absence of a functional NDUFS4Hs subunit (AQDQBt/NUYMYl) has been shown to interfere with complex I assembly resulting in formation of a ~830-kDa subcomplex [20]. Analysis of NDUFS4-knockout mouse models suggested an important function of the subunit in connecting the N-module to the peripheral arm [21,22]. A complex I subassembly of similar size was also identified in patient cell lines carrying a truncated NDUFS6Hs protein (13 kDaBt/NUMMYl) [23]. GFP tagging of complex I subunits indicated that the accessory subunit NDUFA12Hs is added in the late stage of assembly together with the central subunits NDUFV1Hs (51-kDaBt) and NDUFV2Hs (24-kDaBt) of the N-module [24]. Interestingly, NUYMYl/NDUFS4Hs/AQDQBt, NUMMYl/NDUFS6Hs/13-kDaBt and N7BMYl/NDUFA12Hs/B17.2Bt represent the limited subgroup of accessory subunits that is already present in Alphaproteobacteria, e.g. Paracoccus denitrificans [13]. It has been suggested that the NDUFA9Hs (39-kDaBt/NUEMYl) subunit is involved in attachment of the peripheral arm to the membrane arm of complex I [25] and deletion of the corresponding NUEM subunit in Y. lipolytica resulted in a serious assembly defect [14]. A central function for complex I assembly was demonstrated for the STMD subunit orthologous to NDUFA1Hs/MWFEBt/NIMMYl using an inducible expression system in a Chinese-hamster ovary cell line [26].

Two major structural breakpoints are frequently observed in complex I either unintentionally during protein purification or during directed dissection of the holo-complex into subcomplexes [3,18,27,28]. Harsh treatment with LDAO (N,N-dimethyldodecylamine-N-oxide) was reported to detach the matrix arm or major parts of it as subcomplex Iλ [19,27]. A modified version of the LDAO treatment resulted in formation of subcomplex Iδ that lacked major parts of the PP-module including central subunits ND1 and ND3 at the interface to the matrix arm but still maintained a connection to the PD-module [3]. Accessory subunits must play a central role in linking matrix arm and PD-module in subcomplex Iδ and a critical function for subunit NUJMYl (NDUFA11Hs/B14.7Bt) has been suggested [3]. The interface of the PD-module and the PP-module is the second major breakpoint in mitochondrial complex I [18]. Deletion of subunit NB8MYl was shown to detach the complete PD-module [29], highlighting the importance of accessory subunits for integrity of the complex.

Signal transduction and regulation

Phosphorylation of complex I subunits and cAMP/PKA (protein kinase A) regulation

Constitutive and stimulated phosphorylation was demonstrated for several accessory subunits, but for none of the central complex I subunits. Steady-state phosphorylation in native complex I was reported for the 42-kDaBt subunit (NDUFA10Hs) [3032], the B16.6Bt subunit [NB6MYl/NDUFA13Hs; also known as GRIM-19 (gene associated with retinoid/interferon-induced mortality 19)] [32], the B14.5aBt subunit (NUZMYl/NDUFA7Hs) [33] and the B14.5bBt subunit (NDUFC2Hs) [32]. Recently, phosphorylation of subunit NDUFB10Hs (NIDMYl/PDSWBt) by Src kinase was observed in cancer cells [34]. Radiolabelling of an 18-kDa protein assigned to subunit NDUFS4Hs (NUYMYl/AQDQBt) by PKA was first described and linked with stimulation of complex I activity by Papa and colleagues (reviewed in [35]). However, the identity of the labelled protein was challenged by Chen et al. [36] who identified subunit ESSSBt (NDUFB11Hs/NESMYl) to represent the 18-kDa species. In the same experiment, cAMP/PKA-dependent phosphorylation of subunit MWFEBt (NIMMYl/NDUFA1Hs) was demonstrated. Phosphorylation of subunit ESSS after cAMP/PKA treatment of bovine heart mitochondria was confirmed [32]; however, the physiological significance remains unclear because the phosphorylated serine residue is not conserved throughout even in mammalian complex I [36]. The impact of phosphorylation of subunits ESSS and MWFE on complex I assembly was investigated by site-directed mutagenesis [37]. Evidence for phosphorylation of subunit NDUFS4Hs (NUYMYl/AQDQBt) in isolated complex I is still lacking, but it has been pointed out that the subunit of mammalian complex I does contain a conserved canonical PKA phosphorylation site (C-terminal RVSTK) [38] and its functional significance was tested experimentally [38]. The mechanism of complex I regulation by phosphorylation of NDUFS4Hs (NUYMYl/AQDQBt) has been suggested to involve stimulation of mitochondrial precursor protein import and maturation of the subunit permitting assembly into nascent complex I or exchange of subunit(s) of damaged enzyme [39,40].

GRIM-19, STAT3 and the IFN/RA pathway

Investigating the growth-suppressive action of the combination of IFNβ (interferon β) and RA (all-trans-retinoic acid) Angell et al. [41] identified GRIM-19 as a cell death regulatory gene product. Overexpression of GRIM-19 enhanced IFN/RA-induced cell death. In contrast, antisense knockdown protected against cell death in response to IFN/RA [41]. The functional characteristic of GRIM-19 as a tumour-suppressor gene and its role in tumorigenesis has been reviewed recently [42]. The bovine homologue of GRIM-19 was identified as accessory subunit B16.6Bt of mitochondrial complex I [43] and the presence of GRIM-19/NDUFA13Hs as a bona fide subunit of human complex I was confirmed later [6]. In line with this finding, but in contrast with a previously determined nuclear localization [41], GRIM-19 has been found to reside primarily in mitochondria [44]. Tight association of subunit NDUFA13Hs (NB6MYl/B16.6Bt; GRIM-19) with the matrix arm in subcomplex Iλ and the presence of one predicted transmembrane segment suggests a position in the PP-module of the membrane arm of complex I [3,43]. Gene deletion resulted in severe disruption of complex I assembly causing early embryonic lethality [44]. Functional domains of the subunit were dissected by truncation, deletions and point mutations [41,45]. The homologous NB6M subunit of Y. lipolytica complex I lacks part of the functionally important C-terminal domain [1]. It has been suggested that GRIM-19 is a ‘dual-function’ protein and might play a role as a complex I subunit and as a cell death regulatory protein, but the link between these two functions, if any, remains to be established. Two studies independently demonstrated the interaction of GRIM-19 with STAT3 (signal transducer and activator of transcription 3), a latent cytoplasmic transcription factor that is activated by cytokines and growth factors, but different modes of interaction have been suggested [46,47]. Interestingly, GRIM-19 is the target of several viral factors that interfere with its central function in regulation of cell death [48,49]. A 2.7 kb non-coding RNA from HCMV (human cytomegalovirus) has been reported to interact with complex I via GRIM-19 protecting infected cells against apoptosis, apparently by preventing relocalization of the complex I subunit to the nucleus [50]. In contrast, a mechanism for IFN/RA-linked induction of apoptosis with a central function of ROS (reactive oxygen species) overproduction and excluding shuttling of GRIM-19 to the nucleus has been suggested in [51]. Recently, the unprecedented presence of STAT3 in mitochondria and STAT3-dependent modulation of mitochondrial energy metabolism has been demonstrated [5254]. However, very low relative abundance renders significant regulatory effects by direct interaction of STAT3 with complex I unlikely [55]. In conclusion, a clear and consistent picture reconciling all observations on the function of GRIM-19 is still lacking.

A (active)–D (deactive) transition

Mitochondrial complex I from various species has been shown to undergo a reversible A–D transition and the A and D forms of complex I can be distinguished by differential accessibility of a specific cysteine residue in the long loop connecting transmembrane helices 1 and 2 of subunit ND3 [56]. It has been suggested that the fungal 29.9 kDa subunit corresponding to subunit NUFMYl/NDUFA5Hs/B13Bt is involved in modulation of the A–D transition [57]. Recently, differential cross-linking in the A and D states has been observed for the ND3 and the 39-kDaBt (NDUFA9Hs/NUEMYl) subunits [58], suggesting a position at the interface between the membrane arm and the peripheral arm.

Acyl carrier proteins and biosynthetic pathways

The small and highly acidic SDAPBt subunit (NDUFAB1Hs) of bovine complex I was identified as an acyl carrier protein, and the presence of a covalently attached phosphopantheteine prosthetic group was demonstrated [59]. In contrast with human and bovine complex I, Y. lipolytica complex I comprises two acyl carrier protein subunits: ACPM1 and ACPM2 [60]. Deletion of ACPM1Yl appears to be lethal for Y. lipolytica, whereas deletion of ACPM2Yl strongly interferes with complex I assembly [60]. The latter observation is in agreement with results obtained for Neurospora crassa [61]. Given their high sequence similarity, the lack of cross-complementation between ACPM1 and ACPM2 in Y. lipolytica complex I seems remarkable.

Mitochondria harbour all of the necessary functional elements for fatty acid synthesis resembling the type II mode of their bacterial ancestors (reviewed in [62]). In this context, two functions involving mitochondrial acyl carrier proteins are discussed. Several lines of evidence suggest mitochondrial synthesis of octanoic acid as a precursor of lipoic acid, a prosthetic group of, e.g., the mitochondrial pyruvate dehydrogenase and 2-oxoglutarate (α-ketoglutarate) dehydrogenase complexes. Lipoic acid administration fails to compensate for functional disruption of endogenous cofactor synthesis [63]. The second or alternative function is synthesis of longer-chain fatty acids [64] that might be critical for repair of damaged membrane lipids [61,65] or modification of proteins, e.g. myristoylation. It should be noted that the function of the SDAP subunit is very likely to not be dependent on a physical link with complex I as the major fraction of the polypeptide was detected in free form in the mitochondrial matrix [66]. Moreover, none of the three ACPMs detected in Arabidopsis thaliana is associated with complex I [67], and the presence of an ACPM was established in Saccharomyces cerevisiae, a species lacking respiratory complex I [68].

Pathogenic mutations and complex I dysfunction

Oxidative stress is associated with neurodegenerative human diseases and has been suggested to be a key determinant in biological aging [69,70]. Several complex I subunits are targeted by reactive nitrogen species including accessory subunits B15Bt (NDUFB4Hs/NB5MYl), B14Bt (NDUFA6Hs/NB4MYl) and B17.2Bt (NDUFA12Hs/N7BMYl) [71]. Induction of necrotic cell death was found to be linked with nitration of accessory subunit NDUFB8Hs (ASHIBt/NIAMYl) [72].

All accessory subunits and the seven central subunits located in the peripheral arm as well as all complex I assembly factors are nuclear-encoded. Pathogenic mutations in nuclear genes have been reviewed recently [8], and diseases linked with dysfunction of accessory complex I subunits are summarized in Table 1. Nuclear mutations causing severe complex I defects were reported for eight accessory subunits. In most cases, they cause Leigh or Leigh-like syndrome, a multisystemic and progressive neurodegenerative disorder. Subunit NDUFS4Hs stands out as a hotspot with 14 patients and ten affected families described in the literature [73,74]. These numbers are comparable with the highest frequency of observations for central subunits NDUFS1Hs (75-kDaBt subunit, ten cases), NDUFS2Hs (49-kDaBt subunit, 15 cases) and NDUFV1Hs (51-kDaBt subunit, 17 cases) [8].

Summary and outlook

A substantial fraction of the total mass of mitochondrial complex I is represented by accessory subunits, and evidence is accumulating that they are integral and indispensable components of the enzyme complex. The focus of future research will be to gain insights into the functional and structural interaction of accessory and central subunits at the molecular level to comprehensively understand the striking complexity of mitochondrial complex I.

Bioenergetics in Mitochondria, Bacteria and Chloroplasts: Third Joint German/UK Bioenergetics Conference, a Biochemical Society Focused Meeting held at Schloss Rauischholzhausen, Ebsdorfergrund, Germany, 10–13 April 2013. Organized and Edited by Fraser MacMillan (University of East Anglia, Norwich, U.K.) and Thomas Meier (Max Planck Institute of Biophysics, Frankfurt am Main, Germany).

Abbreviations

     
  • A

    active

  •  
  • ACPM

    mitochondrial acyl carrier protein

  •  
  • Bt

    Bos taurus

  •  
  • D

    deactive

  •  
  • GRIM-19

    gene associated with retinoid/interferon-induced mortality 19

  •  
  • Hs

    Homo sapiens

  •  
  • IFN

    interferon

  •  
  • LDAO

    N,N-dimethyldodecylamine-N-oxide

  •  
  • MTMD

    multiple transmembrane domain

  •  
  • N-module

    NADH oxidation module

  •  
  • PD-module

    distal proton pump module

  •  
  • PKA

    protein kinase A

  •  
  • PP-module

    proximal proton pump module

  •  
  • Q-module

    ubiquinone reduction module

  •  
  • RA

    all-trans-retinoic acid

  •  
  • STAT3

    signal transducer and activator of transcription 3

  •  
  • STMD

    single transmembrane domain

  •  
  • Yl

    Yarrowia lipolytica

We thank Heike Angerer and Ulrich Brandt for critically reading the paper before submission and for discussions.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft [grant number ZI 552/3-1] and the Cluster of Excellence Frankfurt ‘Macromolecular Complexes’.

References

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