Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin–proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.

The energetic requirements of neuronal excitability, synaptic activity and plasticity are extensive and are almost exclusively fulfilled by mitochondrial oxidative phosphorylation (OXPHOS) [1]. Mitochondria are often trafficked long distances to meet spatiotemporal adenosine triphosphate (ATP) requirements and dynamic mechanisms determine mitochondrial localisation to best satisfy local demands of the neurone. It is also now clear that, during the lifetime of a neurone, mitochondria can become dysfunctional to the extent they cannot maintain a proton motive force sufficient for ATP generation. Cellular mechanisms engage to remove damaged mitochondria and replenish the mitochondrial pool. These cycles of mitochondrial fusion and fission can become defective in neurodegenerative disorders and consequent accumulation of damaged components within mitochondria can adversely affect mitochondrial function and cellular homeostasis.

Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are pathologically similar, progressive neurodegenerative proteinopathies [2] (Figure 1). Proteinopathy refers to a disease-causing conformational change in a protein that normally has other roles in cell biology. Such proteins undergo pathogenic misfolding and oligomerisation into higher-order structures, revealing self-templating conformations, and have an ability to undergo prion-like spreading between cells, together resulting in toxin gain- or loss-of-function [2,3]. Misfolded proteins can adversely affect mitochondria, either through a direct association, damaging mitochondrial DNA, altering trafficking and dynamics, deregulating bioenergetics and quality control pathways or promoting mitochondria-dependent cell death pathways. Mitochondrial dysfunction as a cause or a consequence of neurodegenerative disease pathogenesis is still debated and a self-perpetuating feed-forward toxic cycle may exist (Figure 2).

Pathological overlap of proteinopathies in different neurodegenerative diseases.

Figure 1.
Pathological overlap of proteinopathies in different neurodegenerative diseases.

Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; DLB, dementia with Lewy bodies; MSA, multiple systems atrophy; PD, Parkinson's disease; PDD, Parkinson's disease dementia; TDP-43, TAR DNA-binding protein 43; FUS, fused in sarcoma.

Figure 1.
Pathological overlap of proteinopathies in different neurodegenerative diseases.

Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; DLB, dementia with Lewy bodies; MSA, multiple systems atrophy; PD, Parkinson's disease; PDD, Parkinson's disease dementia; TDP-43, TAR DNA-binding protein 43; FUS, fused in sarcoma.

Close modal

Reciprocal relationship between mitochondrial function and protein misfolding.

Figure 2.
Reciprocal relationship between mitochondrial function and protein misfolding.

Mitochondrial function is adversely affected by toxic misfolded proteins. Additionally, mitochondrial function is necessary for correct protein folding and processing in neurodegenerative proteinopathies.

Figure 2.
Reciprocal relationship between mitochondrial function and protein misfolding.

Mitochondrial function is adversely affected by toxic misfolded proteins. Additionally, mitochondrial function is necessary for correct protein folding and processing in neurodegenerative proteinopathies.

Close modal

Mitochondrial relationship with amyloid β and tau

AD is the most prevalent proteinopathy, characterised by accumulation of extracellular plaques containing amyloid β (Aβ) and intracellular tangles of tau. Aβ and tau both have detrimental effects on mitochondria [4]. Disruptions in mitochondrial DNA maintenance, protein import, electron transport chain (ETC) activity and redox balance are all consequences of Aβ-induced toxicity [512] (Figure 3 and Table 1). Mitochondrial localisation of Aβ peptide has been observed, albeit the exact sub-mitochondrial topology remains less well defined [13,14] and, indeed, Aβ may be produced at the mitochondrial-associated membrane (MAM) [15], linking mitochondrial–ER contact sites, Ca2+ handling and bioenergetics to Aβ toxicity.

Mitochondrial toxicity of misfolded proteins.

Figure 3.
Mitochondrial toxicity of misfolded proteins.

Red outline depicts misfolded proteins and arrows indicate mitochondrial directed association or toxicity.

Figure 3.
Mitochondrial toxicity of misfolded proteins.

Red outline depicts misfolded proteins and arrows indicate mitochondrial directed association or toxicity.

Close modal
Table 1
Mitochondrial relationship and toxicities with AD associated pathogenic proteins
Pathogenic proteinMitochondrial toxicity or associationReference
Amyloid β Mitochondrial association and protein import: [6,1315,37
  • Localised to mitochondria

  • Aβ peptide import mediated through the TOMM complex

  • Disruption of mitochondrial precursor protein import

  • Interaction with VDAC1 in AD patients, APP and APP/PS1 mice

  • Interaction/co-localisation with OSCP subunit of F1F0-ATP synthase

  • Production at the MAM

 
Mitochondrial DNA maintenance: [5,11,12
  • Deregulation of mitochondrially encoded mRNA transcripts (reduced complex I and increased complexes III and IV)

  • Increased somatic mtDNA mutations in AD brain

  • Oxidative damage to mtDNA

 
ETC and bioenergetics: [610
  • Increased complex I content and decreased complex I activity in tripleAD mice at 12 months

  • Reduced cytochrome C oxidase activity (complex IV) in platelet mitochondria of AD patients and APP overexpressing cell models and mice

  • Reduced ATP, respiratory rate and inner membrane potential

 
Oxidative stress and cell death pathways: [4,6,8,38
  • Oxidative stress, H2O2 production and lipid peroxidation in APP mice

  • Increased superoxide levels APP/PS2 mice and triple AD mice

  • Cytochrome C-mediated apoptosis

  • Increased inner membrane localised CypD in mAPP mice

 
Tau Mitochondrial association and protein import: [6,17,22,23
  • Phospho–tau interaction with VDAC1 in AD patients and APP, APP/PS1 and triple AD transgenic mice

  • N-terminal tau fragment localisation to mitochondria in AD brain

  • N-terminal tau fragment accumulation in human mitochondria isolated from synaptosomes correlates with synaptic changes in AD

 
Deregulated mitophagy: [17,19,20
  • N-terminal tau fragment-mediated net mitochondrial removal and increased mitophagy

  • N-terminal tau fragment-induced trafficking and/or recruitment of parkin and UCHL-1 to mitochondria

  • Increased COX-IV and TOMM20 protein and mtDNA (ratio of mt-Atp6/Rpl13) in AD brain

  • Increased mitochondrial membrane potential (decelerated mitophagy)

 
Mitochondrial trafficking and dynamics: [17,18,21,24,25
  • Hyperphosphorylated tau impaired mitochondrial trafficking

  • Mitochondrial dynamic and trafficking defects following tau overexpression in cultured cells or in in vivo models of tauopathy

  • N-terminal tau fragment-induced mitochondrial redistribution to soma

  • Mislocalisation of DRP1

  • Enhanced levels of OPA1 and mitofusins (mfn1/mfn2) following hTau overexpression

  • Reduced mfn2 ubiquitination in hTau models

  • N-terminal tau fragment-induced mitochondrial fragmentation and cristae remodelling

 
Pathogenic proteinMitochondrial toxicity or associationReference
Amyloid β Mitochondrial association and protein import: [6,1315,37
  • Localised to mitochondria

  • Aβ peptide import mediated through the TOMM complex

  • Disruption of mitochondrial precursor protein import

  • Interaction with VDAC1 in AD patients, APP and APP/PS1 mice

  • Interaction/co-localisation with OSCP subunit of F1F0-ATP synthase

  • Production at the MAM

 
Mitochondrial DNA maintenance: [5,11,12
  • Deregulation of mitochondrially encoded mRNA transcripts (reduced complex I and increased complexes III and IV)

  • Increased somatic mtDNA mutations in AD brain

  • Oxidative damage to mtDNA

 
ETC and bioenergetics: [610
  • Increased complex I content and decreased complex I activity in tripleAD mice at 12 months

  • Reduced cytochrome C oxidase activity (complex IV) in platelet mitochondria of AD patients and APP overexpressing cell models and mice

  • Reduced ATP, respiratory rate and inner membrane potential

 
Oxidative stress and cell death pathways: [4,6,8,38
  • Oxidative stress, H2O2 production and lipid peroxidation in APP mice

  • Increased superoxide levels APP/PS2 mice and triple AD mice

  • Cytochrome C-mediated apoptosis

  • Increased inner membrane localised CypD in mAPP mice

 
Tau Mitochondrial association and protein import: [6,17,22,23
  • Phospho–tau interaction with VDAC1 in AD patients and APP, APP/PS1 and triple AD transgenic mice

  • N-terminal tau fragment localisation to mitochondria in AD brain

  • N-terminal tau fragment accumulation in human mitochondria isolated from synaptosomes correlates with synaptic changes in AD

 
Deregulated mitophagy: [17,19,20
  • N-terminal tau fragment-mediated net mitochondrial removal and increased mitophagy

  • N-terminal tau fragment-induced trafficking and/or recruitment of parkin and UCHL-1 to mitochondria

  • Increased COX-IV and TOMM20 protein and mtDNA (ratio of mt-Atp6/Rpl13) in AD brain

  • Increased mitochondrial membrane potential (decelerated mitophagy)

 
Mitochondrial trafficking and dynamics: [17,18,21,24,25
  • Hyperphosphorylated tau impaired mitochondrial trafficking

  • Mitochondrial dynamic and trafficking defects following tau overexpression in cultured cells or in in vivo models of tauopathy

  • N-terminal tau fragment-induced mitochondrial redistribution to soma

  • Mislocalisation of DRP1

  • Enhanced levels of OPA1 and mitofusins (mfn1/mfn2) following hTau overexpression

  • Reduced mfn2 ubiquitination in hTau models

  • N-terminal tau fragment-induced mitochondrial fragmentation and cristae remodelling

 

Tau is a highly soluble, natively unfolded protein [16]. Tau hyperphosphorylation impairs its ability to bind and stabilise microtubules, and tau aggregation and intraneuronal filaments are common in the pathology of tauopathies (Figure 1). The influence of tau on mitochondrial dynamics and quality control is well documented [1721] (Figure 3). N-terminal tau fragments are associated with mitochondrial functional changes and defects in mitochondrial quality control, and the accumulation of tau fragments in human mitochondria isolated from synaptosomes correlates with synaptic changes observed in AD [17,22,23]. Changes in mitochondrial dynamics are also observed following tau overexpression in cultured cells or in in vivo models of tauopathy [18,24,25] (Table 1).

Some literature suggests that the accumulation of (phospho-)tau and Aβ is a direct consequence of mitochondrial dysfunction [2630]. Perturbations to mitochondrial proteases and chaperones have demonstrated relationships with AD disease markers. Missense mutations in the mitochondrial matrix peptidase, pitrilysin metalloprotease 1 (PITRM1), are associated with Aβ-positive deposits and a slowly progressing neurodegenerative phenotype [31]. In addition, decreased activity in pre-sequence protease (PreP) has been observed in the temporal lobe region of AD patients [32] and has been linked to Aβ processing [33]. Overexpression of heat shock chaperone, mortalin, alleviates Aβ-induced toxicity, while pharmacological inhibition or siRNA down-regulation of mortalin induces DRP-1 (dynamin-related protein 1)-mediated mitochondrial fission and potentiates Aβ-induced mitochondrial and cellular toxicity [34,35]. With respect to pathogenic tau, antioxidant treatment of sod2 nullizygous neonatal mice reverses phospho–tau accumulation, placing mitochondrial oxidative stress upstream of tau pathology [26]. Finally, mitochondrial dysfunction induced by loss of either prohibitin 2 (PHB2), a mitochondrial membrane scaffold protein, or the m-AAA protease subunit, AFG3L2, both results in tau hyperphosphorylation [27,36], potentially linking mitochondrial dysfunction and the cytoskeleton. Taken together, these observations link mitochondrial dynamics, quality control and function to accumulation and toxicity of Aβ and tau.

Mitochondrial toxicity associated with synucleinopathies

PD is characterised by loss of dopaminergic neurones within the substantia nigra pars compacta and reduced dopamine innovation to the striatum. Mitochondrial dysfunction is a prominent pathological feature of both sporadic and familial diseases [3945], and many PD-causing genes have overt mitochondrial phenotypes [4453]. Accumulation of insoluble α-synuclein (α-syn) is a common feature of many clinical phenotypes, known collectively as synucleinopathies [54] (Figure 1).

Mitochondrial localisation of α-syn negatively affects mitochondrial function, morphology and dynamics [46,5560] (Figure 3 and Table 2). Constitutive import of α-syn to mitochondria is transmembrane potential-dependent and is facilitated through a cryptic mitochondrial targeting sequence within the N-terminal region [57]. α-Syn associates with the mitochondrial inner membrane where a direct interaction and toxicity towards mitochondrial complex I has been observed [46,57]. Oligomeric and dopamine-modified α-syn-dependent reduction in protein import occurs via disruption of the association between translocase of the outer mitochondrial membrane (TOMM)-20 and its co-receptor, TOMM22 [61]. As a result, diminished protein import in nigrostriatal neurones impairs mitochondrial function, decreasing respiration and transmembrane potential, and increasing mitochondrial reactive oxygen species (ROS) [61]. Purification of crude mitochondrial preparations has led to the hypothesis that α-syn is, in fact, localised to the MAM [58] and α-syn point mutations reduce mitochondria–ER contacts, causing mitochondrial fragmentation [58]. Finally, α-syn has significant effects on mitochondrial quality control and its accumulation is becoming recognised as a consequence of deficient mitophagy [50,62,63]. α-Syn competes with LC3 for cardiolipin on the outer mitochondrial membrane. Cardiolipin facilitates refolding of α-syn oligomers; however, following prolonged exposure, LC3 is recruited. Mutated α-Syn is less able to compete with LC3, contributing to increased mitophagic flux observed in disease cells [64].

Table 2
Mitochondrial toxicities associated with synucleinopathies
Pathogenic proteinMitochondrial toxicity or associationReference
α-Synuclein Mitochondrial association and protein import: [46,5759,61
  • Disruption of TOMM20 and co-receptor interaction leading to inhibition of mitochondrial protein import

  • Localised to MAM

  • Localised to mitochondria in striatum and substantia nigra of PD brain

  • A53T α-synuclein localised to the mitochondria as both monomers and oligomers

 
Mitochondrial dynamics and morphology: [5860,65
  • α-Synuclein-induced mitochondrial fragmentation via effects on ER–mitochondria contact sites

  • α-Synuclein-mediated destabilisation of the spectrin cytoskeleton and mislocalisation of DRP1

  • Mitochondrial fragmentation and disordered cristae following α-synuclein overexpression

  • Wild-type and A53T α-synuclein outer mitochondrial membrane localisation associated with mitochondrial fragmentation

 
ETC and bioenergetics: [46,56,57,66
  • Monomeric and oligomeric A53T α-synuclein-induced complex I dysfunction in dopaminergic midbrain neurones

  • Reduced complex I activity in α-synuclein overexpressing cell lines and PD brain

  • Reduced complex IV activity in spinal neurones of A53T α-synuclein transgenic mice

  • Complex I misassembly in PD brains

 
Deregulated mitophagy:  
  • Enhanced mitophagy in mutant α-synuclein expressing cells following reduced cardiolipin-mediated refolding

 
 
Oxidative stress and cell death pathways: [55,57,66,67
  • N-terminal α-synuclein regulation of mitochondrial membrane permeability

  • Association of α-synuclein with the ANT

  • Increased oxidative stress in α-synuclein overexpressing cell lines

  • Oxidation of complex I in frontal cortex of PD brain

 
Pathogenic proteinMitochondrial toxicity or associationReference
α-Synuclein Mitochondrial association and protein import: [46,5759,61
  • Disruption of TOMM20 and co-receptor interaction leading to inhibition of mitochondrial protein import

  • Localised to MAM

  • Localised to mitochondria in striatum and substantia nigra of PD brain

  • A53T α-synuclein localised to the mitochondria as both monomers and oligomers

 
Mitochondrial dynamics and morphology: [5860,65
  • α-Synuclein-induced mitochondrial fragmentation via effects on ER–mitochondria contact sites

  • α-Synuclein-mediated destabilisation of the spectrin cytoskeleton and mislocalisation of DRP1

  • Mitochondrial fragmentation and disordered cristae following α-synuclein overexpression

  • Wild-type and A53T α-synuclein outer mitochondrial membrane localisation associated with mitochondrial fragmentation

 
ETC and bioenergetics: [46,56,57,66
  • Monomeric and oligomeric A53T α-synuclein-induced complex I dysfunction in dopaminergic midbrain neurones

  • Reduced complex I activity in α-synuclein overexpressing cell lines and PD brain

  • Reduced complex IV activity in spinal neurones of A53T α-synuclein transgenic mice

  • Complex I misassembly in PD brains

 
Deregulated mitophagy:  
  • Enhanced mitophagy in mutant α-synuclein expressing cells following reduced cardiolipin-mediated refolding

 
 
Oxidative stress and cell death pathways: [55,57,66,67
  • N-terminal α-synuclein regulation of mitochondrial membrane permeability

  • Association of α-synuclein with the ANT

  • Increased oxidative stress in α-synuclein overexpressing cell lines

  • Oxidation of complex I in frontal cortex of PD brain

 

Mitochondrial toxicity in ALS and FTD-linked proteinopathies

ALS and FTD share pathological and genetic similarities and potentially common neurodegenerative pathways [68]. Aggregated transactive response DNA-binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are pathological hallmarks of both ALS and FTD (Figure 1). Both are ribonuclear proteins and contain prion-like domains, rich in glycine molecules, increasing their propensity for aggregation and cell-to-cell transmission. Dysfunction in OXPHOS, Ca2+ handling and ROS have all been proposed as key mitochondrially-associated determinants of ALS pathogenesis [69] (Table 3). Furthermore, mitochondrial trafficking defects are responsible for accumulation of defective mitochondria around cell bodies in motor neurones [69].

Table 3
Mitochondrial toxicities for ALS/FTD associated pathogenic proteins
Pathogenic proteinMitochondrial toxicity or associationReference
TDP-43 Mitochondrial association and protein import: [74
  • N-terminal (27 kDa) and C-terminal (30 kDa) fragments of TDP-43 are localised to mitochondria in APP/PS1 mice

 
Mitochondrial dynamics and morphology: [73,75
  • Reduced mfn1 and increased fis1, correlating with increasing TDP-43 expression in brain lysates

  • Morphological and ultrastructural alterations observed in animal models of TDP-43 pathology

  • Mitochondrial fragmentation following mutant TDP-43 overexpression

 
Mitochondrial trafficking: [72,73
  • Mitochondria and organelle redistribution and clustering within cytoplasmic inclusions

 
Deregulated mitophagy: [74
  • TDP-43 knockdown decreases mitophagy

 
FUS Mitochondrial dynamics and morphology: [70,71
  • Disorganised ER and mitochondria within cytoplasmic inclusions of spinal motor neurones

  • Mitochondrial COX-IV-positive aggregates

 
Pathogenic proteinMitochondrial toxicity or associationReference
TDP-43 Mitochondrial association and protein import: [74
  • N-terminal (27 kDa) and C-terminal (30 kDa) fragments of TDP-43 are localised to mitochondria in APP/PS1 mice

 
Mitochondrial dynamics and morphology: [73,75
  • Reduced mfn1 and increased fis1, correlating with increasing TDP-43 expression in brain lysates

  • Morphological and ultrastructural alterations observed in animal models of TDP-43 pathology

  • Mitochondrial fragmentation following mutant TDP-43 overexpression

 
Mitochondrial trafficking: [72,73
  • Mitochondria and organelle redistribution and clustering within cytoplasmic inclusions

 
Deregulated mitophagy: [74
  • TDP-43 knockdown decreases mitophagy

 
FUS Mitochondrial dynamics and morphology: [70,71
  • Disorganised ER and mitochondria within cytoplasmic inclusions of spinal motor neurones

  • Mitochondrial COX-IV-positive aggregates

 

Ubiquitin-positive aggregates are observed in aged, mutant FUS-expressing transgenic animals and correlate with neuronal loss. Aggregates are also positive for mitochondrial cytochrome C oxidase (COX-IV), suggesting that defective mitochondria may be tagged for removal through the mitophagic machinery [70]. Similar pathology has been observed in a single post-mortem analysis of an FUS mutation carrier [71]. C- and N-terminal fragments of TDP-43 have been identified within mitochondria in Amyloid precursor protein (APP)/PS1 mice and mitochondrial dynamic changes, including trafficking and quality control defects, organelle redistribution and clustering within cytoplasmic inclusions, as well as morphological and ultrastructural alterations, are observed in animal models of TDP-43 pathology [7274]. Taken together, these observations suggest a phenotype of dysfunctional, mislocalised and fragmented mitochondria in ALS and FTD (Figure 3).

Despite evidence of mitochondrial dysfunction in the pathology of proteinopathies and exacerbation of neurodegenerative disorders, the exact biochemical, neurotoxic mechanisms of misfolded, aggregated proteins remain poorly understood. Protecting mitochondrial function therefore may be one plausible drug discovery strategy for neuroprotective or disease-modifying end-points.

Inhibition of mitochondrial permeability transition pore opening

Mitochondrial permeability transition pore (mPTP) opening has been implicated as a major cell death pathway in multiple neurodegenerative diseases [7678]. A shift in the mitochondrial redox balance towards oxidative stress, coupled with Ca2+ overload, triggers opening of the mPTP leading to osmotic swelling, uncoupling of electron transport and metabolic collapse [7986]. The mitochondrial matrix enzyme, cyclophilin D (CypD), is a known positive regulator of mPTP opening [86]. Genetic ablation or pharmacological inhibition of CypD desensitises the pore to Ca2+, restricting pore opening [85,86]. Direct binding between Aβ and CypD links amyloid toxicity to mPTP opening in AD [38,87] and CypD deficiency corrects mitochondrial trafficking defects observed in AD models [88]. Previous literature supports a role for the F1F0-ATP synthase in pore formation [89,90], suggesting that the oligomycin-sensitivity conferring protein (OSCP) serves as a docking site for CypD [90]. Interestingly, OSCP is decreased during AD progression and may directly interact with Aβ [37]. Given the relationship between CypD, OSCP, Aβ and the propensity for mPTP opening, it is plausible that targeting these processes may have clinical benefits. Indeed, recently, phenotypic screening approaches have identified mPTP inhibitors and CypD-binding compounds in a model of Aβ-induced mPTP opening [9194]. Overexpression of an N-terminal region of α-syn has also been observed to regulate mitochondrial membrane permeability [67], linking mPTP to synucleinopathies. Moreover, following overexpression, α-syn associates with the adenine nucleotide translocase (ANT), another putative pore component [95,96]. Interestingly, pharmacological inhibition of ANT partially reverses the associated α-syn-induced mitochondrial toxicity [97].

Homology within the cyclophilin isoenzyme family makes selective targeting of CypD therapeutically challenging [98]. Moreover, since CypD does not constitute a principal pore component, and effects are indirect, mitochondria remain capable of permeability transition given enough stimuli [86,99]. CypD confers sensitivity to the mPTP inhibitor, cyclosporin A (CsA) [85,100], and number of CsA analogues have been developed [101,102]. CsA and its derivatives are large molecular mass natural products and penetrate the blood–brain barrier poorly, limiting efficacy in neurodegenerative disease. Many groups have developed CypD-independent inhibitors [103107], but to date, none, as far as we are aware, have been tested in models of neurodegenerative disease.

Activating mitophagy to improve mitochondrial function in neurodegenerative proteinopathies

Dysfunctional lysosomal and proteasomal degradation pathways have been implicated in neurodegenerative diseases. A selective form of macroautophagy, termed mitophagy, is responsible for the clearance of defective mitochondria from cells [44,45,108110]. PTEN-induced putative kinase 1 (PINK1) and parkin are regulators of mitophagy and are integral to a mechanism that identifies and tags defective mitochondria for removal [110,111] (Figure 4). The association between mutations in these proteins and dysfunction in the mitophagy pathway has direct implications in both familial and sporadic PD [43,51,112].

Defective mitochondria are removed from the cell by mitophagy.

Figure 4.
Defective mitochondria are removed from the cell by mitophagy.

In healthy mitochondria, mitophagy proceeds at a slow rate due to the low abundance of ubiquitinated mitochondrial proteins, PINK1 import and degradation. PINK1 is stabilised on the OMM following mitochondrial depolarisation and phosphorylates both parkin and ubiquitin. Parkin is activated and translocates to mitochondria. Parkin ubiquitinates outer membrane proteins which then serve as targets for autophagic adaptor proteins and mitochondria are then cleared through the autophagic machinery. Abbreviations: IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; TIMM, translocase of the inner mitochondrial membrane; MPP, mitochondrial processing peptidase; MTS, mitochondrial targeting sequence; TOMM, translocase of the outer mitochondrial membrane; Ub, ubiquitin.

Figure 4.
Defective mitochondria are removed from the cell by mitophagy.

In healthy mitochondria, mitophagy proceeds at a slow rate due to the low abundance of ubiquitinated mitochondrial proteins, PINK1 import and degradation. PINK1 is stabilised on the OMM following mitochondrial depolarisation and phosphorylates both parkin and ubiquitin. Parkin is activated and translocates to mitochondria. Parkin ubiquitinates outer membrane proteins which then serve as targets for autophagic adaptor proteins and mitochondria are then cleared through the autophagic machinery. Abbreviations: IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; TIMM, translocase of the inner mitochondrial membrane; MPP, mitochondrial processing peptidase; MTS, mitochondrial targeting sequence; TOMM, translocase of the outer mitochondrial membrane; Ub, ubiquitin.

Close modal

PINK1 and parkin function may be necessary for α-syn clearance. Preceding neurodegeneration, α-syn A53T transgenic mice accumulate neuronal inclusions containing mitochondrial remnants and autophagic markers which increase in size and number with PINK1 or parkin knockout [62]. PINK1 loss-of-function potentiates the A53T phenotype, decreasing lifespan and enhancing movement deficits and protein aggregation [63]. Similarly, iPSCs from mutant PINK1/parkin carriers accumulate cytoplasmic inclusions and insoluble α-syn, a phenotype which can be partially corrected following PINK1 re-expression [50]. Interestingly, following mitochondrial uncoupling, autophagic α-syn removal is reduced and the likelihood of aggregate formation in oligodendrocytes is enhanced, suggesting that mitochondrial damage over time may play a role in α-syn accumulation [48]. Finally, a novel mechanism of PINK1 protection in α-syn models has been proposed as being mediated through protein phosphatase 2A activity [113].

Mitophagy has been linked to both Aβ and tau in AD. PINK1 is down-regulated in AD patients and in transgenic AD models [114]. Furthermore, the absence of PINK1 augments the mutant APP phenotype and stereotaxic injection of rAAV2–PINK1 into the hippocampus of mutant APP mice significantly reduced Aβ compared with control, improving synaptic function and memory [114]. An association between deficient mitophagy and abnormal tau accumulation has been found in AD patient brain homogenate and transgenic mice. This deficit can be rescued by up-regulating parkin expression [20]. Exogenous parkin has also been found to decrease Aβ levels in vitro and Aβ-induced plaque formation in transgenic mice [115117].

Parkin activation may be a promising strategy to enhance mitophagy in disease models. Nilotinib, originally discovered as a tyrosine kinase inhibitor, increases parkin abundance and ubiquitination, potentially increasing parkin recycling via the proteasome [118]. Nilotinib-mediated c-ABL inhibition also prevents parkin tyrosine phosphorylation, resulting in release of parkin auto-inhibition and demonstrating protection in PD models [119]. Additionally, nilotinib has been demonstrated to increase the parkin–beclin 1 interaction and increase clearance of Aβ in transgenic APP mice following chronic treatment [120]. Finally, with respect to ALS and FTD, motor and cognitive deficits measured in TDP-43 transgenic mice have also been reversed using nilotinib [121].

Deubiquitinating (deubiquitinase; DUB) enzymes in neurodegenerative proteinopathies

Down-regulation of the ubiquitin–proteasome system (UPS) is common across neurodegenerative diseases and promoting UPS activity is an emerging strategy for the treatment of proteinopathies. Deubiquitinases (DUBs) hydrolyse isopeptide bonds covalently binding ubiquitin to proteins, regulating degradation, localisation or activity. Multiple DUBs regulate mitochondrial function [122126]. Ubiquitin-specific protease 15 (USP15) and USP30 both antagonise parkin-mediated mitophagy [122,125]. USP30 is the only DUB exclusively localised to mitochondria [127], tethered to the outer mitochondrial membrane. USP30 deubiquitinates parkin substrates, including TOMM20 and MIRO1 [122], and inhibition has been proposed to enhance parkin-mediated mitophagy [128,129] (Figure 4). In one study, USP35 was also found to oppose parkin-mediated mitophagy, with both a distinct mechanism to USP30 and lack of influence on the translocation of parkin [124]. USP8 enhances mitophagy by removing lysine-6-linked ubiquitin from parkin, promoting its turnover [126]. However, confusingly, USP8 knockout also limits toxicity in an α-syn model in Drosophila melanogaster [130]. Other DUBs localise to mitochondria, albeit not exclusively; Ataxin-3 [131,132] and the X-chromosome-linked deubiquitinase, USP9x [132] have demonstrated mitochondrial localisation under specific conditions. USP9x deubiquitinates α-syn and silencing increases the abundance of mono-ubiquitinated α-syn, enhancing its propensity for aggregation [133].

Eliminating ROS in neurodegenerative proteinopathies

Mitochondria are a principal source of cellular ROS. ROS are generated as a by-product of OXPHOS and their abundance presents a fine balance between signalling and toxicity. Much interest has focussed around limiting oxidative stress in neurodegenerative disease. Exogenous expression of a mitochondrially targeted catalase decreases monomeric and oligomeric Aβ and Aβ plaques in mice carrying the APP KM670/671NL (Swedish) mutation [134]. Synthetic analogues of mitochondrial coenzyme Q10 prevent Aβ oligomer-induced changes in mitochondrial mRNA transcript expression, protecting cells against oligomeric Aβ damage [135]. Although perturbation of ROS in preclinical models has so far proved beneficial, to date translation to human disease has been challenging and yielded multiple clinical failures across multiple neurodegenerative diseases [136]. Interestingly, the antioxidant MitoQ has been assessed in many models of ageing and neurodegenerative disease. MitoQ is a redox active ubiquinone, targeted to mitochondria [137]. MitoQ has demonstrated positive effects in an SOD1G93A ALS mouse model [138], a triple transgenic AD mouse [139] and in models of AD in Caenorhabditis elegans [140], together linking mitochondrial ROS and proteinopathy-related neuropathologies. MitoQ is currently in clinical trials testing the efficacy for improving vascular, motor and cognitive function in middle-aged and older adults (NCT02597023).

Compelling evidence suggests that mitochondrial dysfunction plays a significant role in neurodegenerative proteinopathies. Neuronal ATP is provided almost exclusively through mitochondrial OXPHOS, and complicated processes controlling mitochondrial dynamics, redox equilibrium, protein import and mitochondrial quality control work in concert to meet spatiotemporal bioenergetic demands. Aberrant misfolded proteins disrupt these processes, triggering mitochondrial dysfunction and having wider effects on cellular homeostasis.

Numerous disease-modifying strategies targeting mitochondria are currently under investigation. Further development of mPTP inhibitors is warranted due to the emerging evidence of the involvement of Ca2+ homeostasis, ROS and mPTP opening in multiple neurodegenerative diseases. Accelerating removal of damaged mitochondria has been proposed as a novel disease-modifying strategy not only in PD, but in many proteinopathies. Identification of a mechanism to enhance mitophagy may demand increased understanding of DUB biology and the substrate diversity and selectivity of these enzymes. Clinical trials of mitochondrially targeted antioxidants will provide proof-of-concept concerning ROS manipulation. Taken together, thoroughly understanding the mitochondrial relationship with neurodegenerative proteinopathies is likely to pave the way for the development of targeted therapies, potentially modifying the disease course of these progressive degenerative disorders.

AD

Alzheimer's disease

ALS

amyotrophic lateral sclerosis

ANT

adenine nucleotide translocase

APP

amyloid precursor protein

ATP

adenosine triphosphate

amyloid β

COX

cytochrome C oxidase

CsA

cyclosporin A

CypD

cyclophilin D

DRP-1

dynamin-related protein 1

DUB

deubiquitinase

ETC

electron transport chain

fis1

mitochondrial fission 1

FTD

frontotemporal dementia

FUS

fused in sarcoma

MAM

mitochondrial-associated membrane

mPTP

mitochondrial permeability transition pore

OPA-1

optic atrophy 1

OSCP

oligomycin-sensitivity conferring protein

OXPHOS

oxidative phosphorylation

PD

Parkinson's disease

PINK1

PTEN-induced putative kinase 1

ROS

reactive oxygen species

TDP-43

transactive response DNA-binding protein 43 kDa

TOMM

translocase of the outer mitochondrial membrane

UPS

ubiquitin–proteasome system

USP

ubiquitin-specific protease

α-syn

α-synuclein

T.B. and A.R.H. wrote the manuscript.

The authors thank Jim Staddon for helpful comments and advice in the course of manuscript preparation.

T.B. and A.R.H. are employees of Eisai Ltd.

1
Silver
,
I.
and
Erecińska
,
M.
(
1998
) Oxygen and ion concentrations in normoxic and hypoxic brain cells. In
Oxygen Transport to Tissue XX
(
Hudetz
,
A.G.
,
Bruley
,
D.F.
, eds), pp.
7
16
.
Springer
,
Boston, MA
2
Bayer
,
T.A.
(
2015
)
Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?
Eur. Neuropsychopharmacol.
25
,
713
724
3
Ugalde
,
C.L.
,
Finkelstein
,
D.I.
,
Lawson
,
V.A.
and
Hill
,
A.F.
(
2016
)
Pathogenic mechanisms of prion protein, amyloid-β and α-synuclein misfolding: the prion concept and neurotoxicity of protein oligomers
.
J. Neurochem.
139
,
162
180
4
Cardoso
,
S.M.
,
Swerdlow
,
R.H.
and
Oliveira
,
C.R.
(
2002
)
Induction of cytochrome c-mediated apoptosis by amyloid β 25–35 requires functional mitochondria
.
Brain Res.
931
,
117
125
5
Manczak
,
M.
,
Park
,
B.S.
,
Jung
,
Y.
and
Reddy
,
P.H.
(
2004
)
Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage
.
Neuromolecular Med.
5
,
147
162
6
Manczak
,
M.
and
Reddy
,
P.H.
(
2012
)
Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease
.
Hum. Mol. Genet.
21
,
5131
5146
7
Rhein
,
V.
,
Baysang
,
G.
,
Rao
,
S.
,
Meier
,
F.
,
Bonert
,
A.
,
Müller-Spahn
,
F.
et al
. (
2009
)
Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells
.
Cell. Mol. Neurobiol.
29
,
1063
1071
8
Rhein
,
V.
,
Song
,
X.
,
Wiesner
,
A.
,
Ittner
,
L.M.
,
Baysang
,
G.
,
Meier
,
F.
et al.
(
2009
)
Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice
.
Proc. Natl Acad. Sci. U.S.A.
106
,
20057
20062
9
Parker
, Jr,
W.D.
,
Filley
,
C.M.
and
Parks
,
J.K.
(
1990
)
Cytochrome oxidase deficiency in Alzheimer's disease
.
Neurology
40
,
1302
1303
10
Parker
,
W.D.
,
Ba,
J.P.
,
Filley
,
C.M.
and
Kleinschmidt-DeMasters
,
B.K.
(
1994
)
Electron transport chain defects in Alzheimer's disease brain
.
Neurology
44
,
1090
1091
11
Lin
,
M.T.
,
Simon
,
D.K.
,
Ahn
,
C.H.
,
Kim
,
L.M.
and
Beal
,
M.F.
(
2002
)
High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain
.
Hum. Mol. Genet.
11
,
133
145
12
Coskun
,
P.E.
,
Beal
,
M.F.
and
Wallace
,
D.C.
(
2004
)
Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication
.
Proc. Natl Acad. Sci. U.S.A.
101
,
10726
10731
13
Cenini
,
G.
,
Rub
,
C.
,
Bruderek
,
M.
and
Voos
,
W.
(
2016
)
Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process
.
Mol. Biol. Cell
27
,
3257
3272
14
Hansson Petersen
,
C.A.
,
Alikhani
,
N.
,
Behbahani
,
H.
,
Wiehager
,
B.
,
Pavlov
,
P.F.
,
Alafuzoff
,
I.
et al.
(
2008
)
The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
.
Proc. Natl Acad. Sci. U.S.A.
105
,
13145
13150
15
Schreiner
,
B.
,
Hedskog
,
L.
,
Wiehager
,
B.
and
Ankarcrona
,
M.
(
2015
)
Amyloid-β peptides are generated in mitochondria-associated endoplasmic reticulum membranes
.
J. Alzheimers Dis.
43
,
369
374
16
Duan
,
A.R.
,
Jonasson
,
E.M.
,
Alberico
,
E.O.
,
Li
,
C.
,
Scripture
,
J.P.
,
Miller
,
R.A.
et al.
(
2017
)
Interactions between tau and different conformations of tubulin: implications for tau function and mechanism
.
J. Mol. Biol.
429
,
1424
1438
17
Amadoro
,
G.
,
Corsetti
,
V.
,
Florenzano
,
F.
,
Atlante
,
A.
,
Ciotti
,
M.T.
,
Mongiardi
,
M.P.
et al.
(
2014
)
AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons
.
Neurobiol. Dis.
62
,
489
507
18
DuBoff
,
B.
,
Götz
,
J.
and
Feany
,
M.B.
(
2012
)
Tau promotes neurodegeneration via DRP1 mislocalization in vivo
.
Neuron
75
,
618
632
19
Corsetti
,
V.
,
Florenzano
,
F.
,
Atlante
,
A.
,
Bobba
,
A.
,
Ciotti
,
M.T.
,
Natale
,
F.
et al.
(
2015
)
NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease
.
Hum. Mol. Genet.
24
,
3058
3081
20
Hu
,
Y.
,
Li
,
X.C.
,
Wang
,
Z.H.
,
Luo
,
Y.
,
Zhang
,
X.
,
Liu
,
X.P.
et al.
(
2016
)
Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin
.
Oncotarget
7
,
17356
17368
21
Li
,
X.-C.
,
Hu
,
Y.
,
Wang
,
Z.-h.
,
Luo
,
Y.
,
Zhang
,
Y.
,
Liu
,
X.-P.
et al.
(
2016
)
Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins
.
Sci. Rep.
6
,
24756
22
Amadoro
,
G.
,
Corsetti
,
V.
,
Stringaro
,
A.
,
Colone
,
M.
,
D'Aguanno
,
S.
,
Meli
,
G.
et al.
(
2010
)
A NH2 tau fragment targets neuronal mitochondria at AD synapses: possible implications for neurodegeneration
.
J. Alzheimers Dis.
21
,
445
470
23
Amadoro
,
G.
,
Corsetti
,
V.
,
Atlante
,
A.
,
Florenzano
,
F.
,
Capsoni
,
S.
,
Bussani
,
R.
et al.
(
2012
)
Interaction between NH-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration
.
Neurobiol. Aging
33
,
833.e1
833.e25
24
Kopeikina
,
K.J.
,
Carlson
,
G.A.
,
Pitstick
,
R.
,
Ludvigson
,
A.E.
,
Peters
,
A.
,
Luebke
,
J.I.
et al.
(
2011
)
Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain
.
Am. J. Pathol.
179
,
2071
2082
25
Stoothoff
,
W.
,
Jones
,
P.B.
,
Spires-Jones
,
T.L.
,
Joyner
,
D.
,
Chhabra
,
E.
,
Bercury
,
K.
et al.
(
2009
)
Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport
.
J. Neurochem.
111
,
417
427
26
Melov
,
S.
,
Adlard
,
P.A.
,
Morten
,
K.
,
Johnson
,
F.
,
Golden
,
T.R.
,
Hinerfeld
,
D.
et al.
(
2007
)
Mitochondrial oxidative stress causes hyperphosphorylation of tau
.
PLoS ONE
2
,
e536
27
Merkwirth
,
C.
,
Martinelli
,
P.
,
Korwitz
,
A.
,
Morbin
,
M.
,
Bronneke
,
H.S.
,
Jordan
,
S.D.
et al.
(
2012
)
Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration
.
PLoS Genet.
8
,
e1003021
28
Silva
,
D.F.
,
Esteves
,
A.R.
,
Oliveira
,
C.R.
and
Cardoso
,
S.M.
(
2011
)
Mitochondria: the common upstream driver of amyloid-β and tau pathology in Alzheimer's disease
.
Curr. Alzheimer Res.
8
,
563
572
29
Iijima-Ando
,
K.
,
Sekiya
,
M.
,
Maruko-Otake
,
A.
,
Ohtake
,
Y.
,
Suzuki
,
E.
,
Lu
,
B.
et al.
(
2012
)
Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1
.
PLoS Genet.
8
,
e1002918
30
Joh
,
Y.
and
Choi
,
W.-S.
(
2017
)
Mitochondrial complex I inhibition accelerates amyloid toxicity
.
Dev. Reprod.
21
,
417
424
31
Brunetti
,
D.
,
Torsvik
,
J.
,
Dallabona
,
C.
,
Teixeira
,
P.
,
Sztromwasser
,
P.
,
Fernandez-Vizarra
,
E.
et al.
(
2016
)
Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration
.
EMBO Mol. Med.
8
,
176
190
32
Alikhani
,
N.
,
Guo
,
L.
,
Yan
,
S.
,
Du
,
H.
,
Pinho
,
C.M.
,
Chen
,
J.X.
et al.
(
2011
)
Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria
.
J. Alzheimers Dis.
27
,
75
87
33
Falkevall
,
A.
,
Alikhani
,
N.
,
Bhushan
,
S.
,
Pavlov
,
P.F.
,
Busch
,
K.
,
Johnson
,
K.A.
et al.
(
2006
)
Degradation of the amyloid β-protein by the novel mitochondrial peptidasome, PreP
.
J. Biol. Chem.
281
,
29096
29104
34
Park
,
S.J.
,
Shin
,
J.H.
,
Jeong
,
J.I.
,
Song
,
J.H.
,
Jo
,
Y.K.
,
Kim
,
E.S.
et al.
(
2014
)
Down-regulation of Mortalin exacerbates Aβ-mediated mitochondrial fragmentation and dysfunction
.
J. Biol. Chem.
289
,
2195
2204
35
Qu
,
M.
,
Zhou
,
Z.
,
Xu
,
S.
,
Chen
,
C.
,
Yu
,
Z.
and
Wang
,
D.
(
2011
)
Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells
.
Brain Res.
1368
,
336
345
36
Kondadi
,
A.K.
,
Wang
,
S.
,
Montagner
,
S.
,
Kladt
,
N.
,
Korwitz
,
A.
,
Martinelli
,
P.
et al.
(
2014
)
Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation
.
EMBO J.
33
,
1011
1026
37
Beck
,
S.J.
,
Guo
,
L.
,
Phensy
,
A.
,
Tian
,
J.
,
Wang
,
L.
,
Tandon
,
N.
et al.
(
2016
)
Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease
.
Nat. Commun.
7
,
11483
38
Du
,
H.
,
Guo
,
L.
,
Zhang
,
W.
,
Rydzewska
,
M.
and
Yan
,
S.
(
2011
)
Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model
.
Neurobiol. Aging
32
,
398
406
39
Bose
,
A.
and
Beal
,
M.F.
(
2016
)
Mitochondrial dysfunction in Parkinson's disease
.
J. Neurochem.
139
(
Suppl 1
),
216
231
40
Luo
,
Y.
,
Hoffer
,
A.
,
Hoffer
,
B.
and
Qi
,
X.
(
2015
)
Mitochondria: a therapeutic target for Parkinson's disease?
Int. J. Mol. Sci.
16
,
20704
20730
41
Osellame
,
L.D.
,
Rahim
,
A.A.
,
Hargreaves
,
I.P.
,
Gegg
,
M.E.
,
Richard-Londt
,
A.
,
Brandner
,
S.
et al.
(
2013
)
Mitochondria and quality control defects in a mouse model of Gaucher disease—links to Parkinson's disease
.
Cell Metab.
17
,
941
953
42
Pickrell
,
A.M.
and
Youle
,
R.J.
(
2015
)
The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease
.
Neuron
85
,
257
273
43
Valente
,
E.M.
,
Abou-Sleiman
,
P.M.
,
Caputo
,
V.
,
Muqit
,
M.M.K.
,
Harvey
,
K.
,
Gispert
,
S.
et al.
(
2004
)
Hereditary early-onset Parkinson's disease caused by mutations in PINK1
.
Science
304
,
1158
1160
44
Clark
,
I.E.
Dodson
,
M.W.
,
Jiang
,
C.
,
Cao
,
J.H.
,
Huh
,
J.R.
,
Seol
,
J.H.
et al.
(
2006
)
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
.
Nature
441
,
1162
1166
45
Park
,
J.
,
Lee
,
S.B.
,
Lee
,
S.
,
Kim
,
Y.
,
Song
,
S.
,
Kim
,
S.
et al.
(
2006
)
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
.
Nature
441
,
1157
1161
46
Chinta
,
S.J.
,
Mallajosyula
,
J.K.
,
Rane
,
A.
and
Andersen
,
J.K.
(
2010
)
Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo
.
Neurosci. Lett.
486
,
235
239
47
Lindström
,
V.
,
Gustafsson
,
G.
,
Sanders
,
L.H.
,
Howlett
,
E.H.
,
Sigvardson
,
J.
,
Kasrayan
,
A.
et al.
(
2017
)
Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
.
Mol. Cell Neurosci.
82
,
143
156
48
Pukaß
,
K.
,
Goldbaum
,
O.
and
Richter-Landsberg
,
C.
(
2015
)
Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of α-synuclein in oligodendroglial cells
.
J. Neurochem.
135
,
194
205
49
Sherer
,
T.B.
,
Betarbet
,
R.
,
Stout
,
A.K.
,
Lund
,
S.
,
Baptista
,
M.
,
Panov
,
A.V.
et al.
(
2002
)
An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered α-synuclein metabolism and oxidative damage
.
J. Neurosci.
22
,
7006
7015
50
Chung
,
S.Y.
,
Kishinevsky
,
S.
,
Mazzulli
,
J.R.
,
Graziotto
,
J.
,
Mrejeru
,
A.
,
Mosharov
,
E.V.
et al.
(
2016
)
Parkin and PINK1 patient iPSC-derived midbrain dopamine neurons exhibit mitochondrial dysfunction and α-synuclein accumulation
.
Stem Cell Rep.
7
,
664
677
51
Hsieh
,
C.-H.
,
Shaltouki
,
A.
,
Gonzalez
,
A.E.
,
Bettencourt da Cruz
,
A.
,
Burbulla
,
L.F.
,
St Lawrence
,
E.
et al.
(
2016
)
Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson's disease
.
Cell Stem Cell
19
,
709
724
52
Burchell
,
V.S.
,
Nelson
,
D.E.
,
Sanchez-Martinez
,
A.
,
Delgado-Camprubi
,
M.
,
Ivatt
,
R.M.
,
Pogson
,
J.H.
et al.
(
2013
)
The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy
.
Nat. Neurosci.
16
,
1257
1265
53
Zhou
,
Z.D.
,
Xie
,
S.P.
,
Sathiyamoorthy
,
S.
,
Saw
,
W.T.
,
Sing
,
T.Y.
,
Ng
,
S.H.
et al.
(
2015
)
F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy
.
Hum. Mol. Genet.
24
,
6314
6330
54
Jellinger
,
K.A.
(
2010
)
Synucleinopathies. Encyclopedia of Movement Disorders
, pp.
203
207
.
Academic Press
,
Oxford
55
Hsu
,
L.J.
,
Sagara
,
Y.
,
Arroyo
,
A.
,
Rockenstein
,
E.
,
Sisk
,
A.
,
Mallory
,
M.
et al.
(
2000
)
α-synuclein promotes mitochondrial deficit and oxidative stress
.
Am. J. Pathol.
157
,
401
410
56
Martin
,
L.J.
,
Pan
,
Y.
,
Price
,
A.C.
,
Sterling
,
W.
,
Copeland
,
N.G.
,
Jenkins
,
N.A.
et al.
(
2006
)
Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death
.
J. Neurosci.
26
,
41
50
57
Devi
,
L.
,
Raghavendran
,
V.
,
Prabhu
,
B.M.
,
Avadhani
,
N.G.
and
Anandatheerthavarada
,
H.K.
(
2008
)
Mitochondrial import and accumulation of α-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain
.
J. Biol. Chem.
283
,
9089
9100
58
Guardia-Laguarta
,
C.
,
Area-Gomez
,
E.
,
Rub
,
C.
,
Liu
,
Y.
,
Magrane
,
J.
,
Becker
,
D.
et al.
(
2014
)
α-synuclein is localized to mitochondria-associated ER membranes
.
J. Neurosci.
34
,
249
259
59
Pozo Devoto
,
V.M.
,
Dimopoulos
,
N.
,
Alloatti
,
M.
,
Pardi
,
M.B.
,
Saez
,
T.M.
,
Otero
,
M.G.
et al
. (
2017
)
αsynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson's disease
.
Sci. Rep.
7
,
5042
60
Nakamura
,
K.
,
Nemani
,
V.M.
,
Azarbal
,
F.
,
Skibinski
,
G.
,
Levy
,
J.M.
,
Egami
,
K.
et al.
(
2011
)
Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein
.
J. Biol. Chem.
286
,
20710
20726
61
Di Maio
,
R.
,
Barrett
,
P.J.
,
Hoffman
,
E.K.
,
Barrett
,
C.W.
,
Zharikov
,
A.
,
Borah
,
A.
et al.
(
2016
)
α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease
.
Sci. Transl. Med.
8
,
342ra78
62
Chen
,
L.
,
Xie
,
Z.
,
Turkson
,
S.
and
Zhuang
,
X.
(
2015
)
A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration
.
J. Neurosci.
35
,
890
905
63
Gispert
,
S.
,
Brehm
,
N.
,
Weil
,
J.
,
Seidel
,
K.
,
Rüb
,
U.
,
Kern
,
B.
et al.
(
2015
)
Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T-SNCA overexpression
.
Hum. Mol. Genet.
24
,
1061
1076
64
Ryan
,
T.
,
Bamm
,
V.V.
,
Stykel
,
M.G.
,
Coackley
,
C.L.
,
Humphries
,
K.M.
,
Jamieson-Williams
,
R.
et al.
(
2018
)
Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
.
Nat. Commun.
9
,
817
65
Ordonez
,
D.G.
,
Lee
,
M.K.
and
Feany
,
M.B.
(
2018
)
α-synuclein induces mitochondrial dysfunction through spectrin and the actin cytoskeleton
.
Neuron
97
,
108
24.e6
66
Keeney
,
P.M.
,
Xie
,
J.
,
Capaldi
,
R.A.
and
Bennett
,
J.P.
(
2006
)
Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled
.
J. Neurosci.
26
,
5256
5264
67
Shen
,
J.
,
Du
,
T.
,
Wang
,
X.
,
Duan
,
C.
,
Gao
,
G.
,
Zhang
,
J.
et al.
(
2014
) α-Synuclein amino terminus regulates mitochondrial membrane permeability
.
Brain Res.
1591
,
14
26
68
Ferrari
,
R.
,
Kapogiannis
,
D.
,
Huey
,
E.D.
and
Momeni
,
P.
(
2011
)
FTD and ALS: a tale of two diseases
.
Curr. Alzheimer Res.
8
,
273
294
69
Muyderman
,
H.
and
Chen
,
T.
(
2014
)
Mitochondrial dysfunction in amyotrophic lateral sclerosis — a valid pharmacological target?
Br. J. Pharmacol.
171
,
2191
2205
70
Huang
,
C.
,
Zhou
,
H.
,
Tong
,
J.
,
Chen
,
H.
,
Liu
,
Y.-J.
,
Wang
,
D.
et al.
(
2011
)
FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration
.
PLoS Genet.
7
,
e1002011
71
Huang
,
E.J.
,
Zhang
,
J.
,
Geser
,
F.
,
Trojanowski
,
J.Q.
,
Strober
,
J.B.
,
Dickson
,
D.W.
et al.
(
2010
)
Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions
.
Brain Pathol.
20
,
1069
1076
72
Shan
,
X.
,
Chiang
,
P.-M.
,
Price
,
D.L.
and
Wong
,
P.C.
(
2010
)
Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice
.
Proc. Natl Acad. Sci. U.S.A.
107
,
16325
16330
73
Xu
,
Y.-F.
,
Gendron
,
T.F.
,
Zhang
,
Y.-J.
,
Lin
,
W.-L.
,
D'Alton
,
S.
,
Sheng
,
H.
et al.
(
2010
)
Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice
.
J. Neurosci.
30
,
10851
10859
74
Davis
,
S.A.
,
Itaman
,
S.
,
Khalid-Janney
,
C.M.
,
Sherard
,
J.A.
,
Dowell
,
J.A.
,
Cairns
,
N.J.
et al.
(
2018
)
TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics
.
Neurosci. Lett.
678
,
8
15
75
Wang
,
W.
,
Li
,
L.
,
Lin
,
W.-L.
,
Dickson
,
D.W.
,
Petrucelli
,
L.
,
Zhang
,
T.
et al.
(
2013
)
The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons
.
Hum. Mol. Genet.
22
,
4706
4719
76
Supnet
,
C.
and
Bezprozvanny
,
I.
(
2010
)
Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease
.
J. Alzheimers Dis.
20
(
Suppl 2
),
S487
S498
77
Supnet
,
C.
and
Bezprozvanny
,
I.
(
2010
)
The dysregulation of intracellular calcium in Alzheimer disease
.
Cell Calcium
47
,
183
189
78
Pivovarova
,
N.B.
and
Andrews
,
S.B.
(
2010
)
Calcium-dependent mitochondrial function and dysfunction in neurons
.
FEBS J.
277
,
3622
3636
79
Haworth
,
R.A.
and
Hunter
,
D.R.
(
1979
)
The Ca2+-induced membrane transition in mitochondria. II. Nature of the Ca2+ trigger site
.
Arch. Biochem. Biophys.
195
,
460
467
80
Szabó
,
I.
,
Bernardi
,
P.
and
Zoratti
,
M.
(
1992
)
Modulation of the mitochondrial megachannel by divalent cations and protons
.
J. Biol. Chem.
267
,
2940
2946
PMID:
[PubMed]
81
Bernardi
,
P.
,
Vassanelli
,
S.
,
Veronese
,
P.
,
Colonna
,
R.
,
Szabó
,
I.
and
Zoratti
,
M.
(
1992
)
Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations
.
J. Biol. Chem.
267
,
2934
2939
PMID:
[PubMed]
82
Scorrano
,
L.
,
Petronilli
,
V.
and
Bernardi
,
P.
(
1997
)
On the voltage dependence of the mitochondrial permeability transition pore. A critical appraisal
.
J. Biol. Chem.
272
,
12295
12299
83
Crompton
,
M.
(
1999
)
The mitochondrial permeability transition pore and its role in cell death
.
Biochem. J.
341
,
233
249
84
Briston
,
T.
,
Roberts
,
M.
,
Lewis
,
S.
,
Powney
,
B.
,
Staddon
,
J.M
,
Szabadkai
,
G.
et al.
(
2017
)
Mitochondrial permeability transition pore: sensitivity to opening and mechanistic dependence on substrate availability
.
Sci. Rep.
7
,
10492
85
Crompton
,
M.
,
Ellinger
,
H.
and
Costi
,
A.
(
1988
)
Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress
.
Biochem. J.
255
,
357
360
PMID:
[PubMed]
86
Baines
,
C.P.
,
Kaiser
,
R.A.
,
Purcell
,
N.H.
,
Blair
,
N.S.
,
Osinska
,
H.
,
Hambleton
,
M.A.
et al.
(
2005
)
Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
.
Nature
434
,
658
662
87
Du
,
H.
,
Guo
,
L.
,
Fang
,
F.
,
Chen
,
D.
,
Sosunov
,
A.A.
,
McKhann
,
G.M.
et al.
(
2008
)
Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease
.
Nat. Med.
14
,
1097
1105
88
Guo
,
L.
,
Du
,
H.
,
Yan
,
S.
,
Wu
,
X.
,
McKhann
,
G.M.
,
Chen
,
J.X.
et al.
(
2013
)
Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer's neurons
.
PLoS ONE
8
,
e54914
89
Giorgio
,
V.
,
Bisetto
,
E.
,
Soriano
,
M.E.
,
Dabbeni-Sala
,
F.
,
Basso
,
E.
,
Petronilli
,
V.
et al.
(
2009
)
Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex
.
J. Biol. Chem.
284
,
33982
33988
90
Giorgio
,
V.
,
von Stockum
,
S.
,
Antoniel
,
M.
,
Fabbro
,
A.
,
Fogolari
,
F.
,
Forte
,
M.
et al.
(
2013
)
Dimers of mitochondrial ATP synthase form the permeability transition pore
.
Proc. Natl Acad. Sci. U.S.A.
110
,
5887
5892
91
Elkamhawy
,
A.
,
Park
,
J.-e.
,
Hassan
,
A.H.E.
,
Pae
,
A.N.
,
Lee
,
J.
,
Park
,
B.-G.
et al.
(
2018
)
Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of Aβ-induced mitochondrial dysfunction in Alzheimer's disease
.
Eur. J. Med. Chem.
144
,
529
543
92
Park
,
J.-e.
,
Elkamhawy
,
A.
,
Hassan
,
A.H.E.
,
Pae
,
A.N.
,
Lee
,
J.
,
Paik
,
S.
et al.
(
2017
)
Synthesis and evaluation of new pyridyl/pyrazinyl thiourea derivatives: neuroprotection against amyloid-β-induced toxicity
.
Eur. J. Med. Chem.
141
,
322
334
93
Valasani
,
K.R.
,
Sun
,
Q.
,
Fang
,
D.
,
Zhang
,
Z.
,
Yu
,
Q.
,
Guo
,
Y.
et al.
(
2016
)
Identification of a small molecule cyclophilin D inhibitor for rescuing Aβ-mediated mitochondrial dysfunction
.
ACS Med. Chem. Lett.
7
,
294
299
94
Kim
,
Y.S.
,
Jung
,
S.h.
,
Park
,
B.-G.
,
Ko
,
M.K.
,
Jang
,
H.-S.
,
Choi
,
K.
et al.
(
2013
)
Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction
.
Eur. J. Med. Chem.
62
,
71
83
95
Woodfield
,
K.
,
Rück
,
A.
,
Brdiczka
,
D.
and
Halestrap
,
A.P.
(
1998
)
Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition
.
Biochem. J.
336
(
Pt 2
),
287
290
96
Richardson
,
A.P.
and
Halestrap
,
A.P.
(
2016
)
Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity
.
Biochem. J.
473
,
1129
1140
97
Zhu
,
Y.
,
Duan
,
C.
,
,
L.
,
Gao
,
H.
,
Zhao
,
C.
,
Yu
,
S.
et al.
(
2011
)
α-Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator
.
Int. J. Biochem. Cell Biol.
43
,
732
741
98
Wang
,
P.
and
Heitman
,
J.
(
2005
)
The cyclophilins
.
Genome Biol.
6
,
226
99
Basso
,
E.
,
Fante
,
L.
,
Fowlkes
,
J.
,
Petronilli
,
V.
,
Forte
,
M.A.
and
Bernardi
,
P.
(
2005
)
Properties of the permeability transition pore in mitochondria devoid of cyclophilin D
.
J. Biol. Chem.
280
,
18558
18561
100
Halestrap
,
A.P.
and
Davidson
,
A.M.
(
1990
)
Inhibition of Ca2+-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase
.
Biochem. J.
268
,
153
160
101
Hansson
,
M.J.
,
Mattiasson
,
G.
,
Månsson
,
R.
,
Karlsson
,
J.
,
Keep
,
M.F.
,
Waldmeier
,
P.
et al.
(
2004
)
The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria
.
J. Bioenerg. Biomembr.
36
,
407
413
102
Tiepolo
,
T.
,
Angelin
,
A.
,
Palma
,
E.
,
Sabatelli
,
P.
,
Merlini
,
L.
,
Nicolosi
,
L.
et al.
(
2009
)
The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1−/− myopathic mice
.
Br. J. Pharmacol.
157
,
1045
1052
103
Schaller
,
S.
,
Paradis
,
S.
,
Ngoh
,
G.A.
,
Assaly
,
R.
,
Buisson
,
B.
,
Drouot
,
C.
et al.
(
2010
)
TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition
.
J. Pharmacol. Exp. Ther.
333
,
696
706
104
Roy
,
S.
,
Šileikyte˙
,
J.
,
Neuenswander
,
B.
,
Hedrick
,
M.P.
,
Chung
,
T.D.Y.
,
Aubé
,
J.
et al.
(
2016
)
N-Phenylbenzamides as potent inhibitors of the mitochondrial permeability transition pore
.
ChemMedChem
11
,
283
288
105
Fancelli
,
D.
,
Abate
,
A.
,
Amici
,
R.
,
Bernardi
,
P.
,
Ballarini
,
M.
,
Cappa
,
A.
et al.
(
2014
)
Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo
.
J. Med. Chem.
57
,
5333
5347
106
Briston
,
T.
,
Lewis
,
S.
,
Koglin
,
M.
,
Mistry
,
K.
,
Shen
,
Y.
,
Hartopp
,
N.
et al.
(
2016
)
Identification of ER-000444793, a cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria
.
Sci. Rep.
6
,
37798
107
Martin
,
L.J.
,
Fancelli
,
D.
,
Wong
,
M.
,
Niedzwiecki
,
M.
,
Ballarini
,
M.
,
Plyte
,
S.
et al.
(
2014
)
GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis
.
Front. Cell. Neurosci.
8
,
433
108
Yang
,
Y.
,
Gehrke
,
S.
,
Imai
,
Y.
,
Huang
,
Z.
,
Ouyang
,
Y.
,
Wang
,
J.-W.
et al.
(
2006
)
Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin
.
Proc. Natl Acad. Sci. U.S.A.
103
,
10793
10798
109
Lemasters
,
J.J.
(
2005
)
Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging
.
Rejuvenation Res.
8
,
3
5
110
Narendra
,
D.
,
Tanaka
,
A.
,
Suen
,
D.-F.
and
Youle
,
R.J.
(
2008
)
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
.
J. Cell Biol.
183
,
795
803
111
Lazarou
,
M.
,
Jin
,
S.M.
,
Kane
,
L.A.
and
Youle
,
R.J.
(
2012
)
Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin
.
Dev. Cell
22
,
320
333
112
Kitada
,
T.
,
Asakawa
,
S.
,
Hattori
,
N.
,
Matsumine
,
H.
,
Yamamura
,
Y.
,
Minoshima
,
S.
et al.
(
1998
)
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
.
Nature
392
,
605
608
113
Yang
,
W.
,
Wang
,
X.
,
Liu
,
J.
,
Duan
,
C.
,
Gao
,
G.
,
Lu
,
L.
et al.
(
2018
)
PINK1 suppresses α-synuclein-induced neuronal injury: a novel mechanism in protein phosphatase 2A activation
.
Oncotarget
9
,
37
53
114
Du
,
F.
,
Yu
,
Q.
,
Yan
,
S.
,
Hu
,
G.
,
Lue
,
L.-F.
,
Walker
,
D.G.
et al.
(
2017
)
PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease
.
Brain
140
,
3233
3251
115
Hong
,
X.
,
Liu
,
J.
,
Zhu
,
G.
,
Zhuang
,
Y.
,
Suo
,
H.
,
Wang
,
P.
et al.
(
2014
)
Parkin overexpression ameliorates hippocampal long-term potentiation and β-amyloid load in an Alzheimer's disease mouse model
.
Hum. Mol. Genet.
23
,
1056
1072
116
Burns
,
M.P.
,
Zhang
,
L.
,
Rebeck
,
G.W.
,
Querfurth
,
H.W.
and
Moussa
,
C.E.-H.
(
2009
)
Parkin promotes intracellular Aβ1–42 clearance
.
Hum. Mol. Genet.
18
,
3206
3216
117
Khandelwal
,
P.J.
,
Herman
,
A.M.
,
Hoe
,
H.-S.
,
Rebeck
,
G.W.
and
Moussa
,
C.E.-H.
(
2011
)
Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Aβ in AD models
.
Hum. Mol. Genet.
20
,
2091
2102
118
Lonskaya
,
I.
,
Hebron
,
M.L.
,
Desforges
,
N.M.
,
Schachter
,
J.B.
and
Moussa
,
C.E.-H.
(
2014
)
Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance
.
J. Mol. Med.
92
,
373
386
119
Ko
,
H.S.
,
Lee
,
Y.
,
Shin
,
J.-H.
,
Karuppagounder
,
S.S.
,
Gadad
,
B.S.
,
Koleske
,
A.J.
et al.
(
2010
)
Phosphorylation by the c-Abl protein tyrosine kinase inhibits Parkin's ubiquitination and protective function
.
Proc. Natl Acad. Sci. U.S.A.
107
,
16691
16696
120
Lonskaya
,
I.
,
Hebron
,
M.L.
,
Desforges
,
N.M.
,
Franjie
,
A.
and
Moussa
,
C.E.H.
(
2013
)
Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance
.
EMBO Mol. Med.
5
,
1247
1262
121
Wenqiang
,
C.
,
Lonskaya
,
I.
,
Hebron
,
M.L.
,
Ibrahim
,
Z.
,
Olszewski
,
R.T.
,
Neale
,
J.H.
et al.
(
2014
)
Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice
.
Hum. Mol. Genet.
23
,
4960
4969
122
Bingol
,
B.
,
Tea
,
J.S.
,
Phu
,
L.
,
Reichelt
,
M.
,
Bakalarski
,
C.E.
,
Song
,
Q.
et al.
(
2014
)
The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy
.
Nature
510
,
370
375
123
Cunningham
,
C.N.
,
Baughman
,
J.M.
,
Phu
,
L.
,
Tea
,
J.S.
,
Yu
,
C.
,
Coons
,
M.
et al.
(
2015
)
USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria
.
Nat. Cell Biol.
17
,
160
169
124
Wang
,
Y.
,
Serricchio
,
M.
,
Jauregui
,
M.
,
Shanbhag
,
R.
,
Stoltz
,
T.
,
Di Paolo
,
C.T.
et al.
(
2015
)
Deubiquitinating enzymes regulate PARK2-mediated mitophagy
.
Autophagy
11
,
595
606
125
Cornelissen
,
T.
,
Haddad
,
D.
,
Wauters
,
F.
,
Van Humbeeck
,
C.
,
Mandemakers
,
W.
,
Koentjoro
,
B.
et al.
(
2014
)
The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy
.
Hum. Mol. Genet.
23
,
5227
5242
126
Durcan
,
T.M.
,
Tang
,
M.Y.
,
Pérusse
,
J.R.
,
Dashti
,
E.A.
,
Aguileta
,
M.A.
,
McLelland
,
G.L.
et al.
(
2014
)
USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin
.
EMBO J.
33
,
2473
2491
127
Nakamura
,
N.
and
Hirose
,
S.
(
2008
)
Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane
.
Mol. Biol. Cell
19
,
1903
1911
128
Thobois
,
S.
(
2015
)
USP30: a new promising target for Parkinson's disease?
Mov. Disord.
30
,
340
129
Yue
,
W.
,
Chen
,
Z.
,
Liu
,
H.
,
Yan
,
C.
,
Chen
,
M.
,
Feng
,
D.
et al.
(
2014
)
A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30
.
Cell Res.
24
,
482
496
130
Alexopoulou
,
Z.
,
Lang
,
J.
,
Perrett
,
R.M.
,
Elschami
,
M.
,
Hurry
,
M.E.D.
,
Kim
,
H.T.
et al.
(
2016
)
Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease
.
Proc. Natl Acad. Sci. U.S.A.
113
,
E4688
E4697
131
Pozzi
,
C.
,
Valtorta
,
M.
,
Tedeschi
,
G.
,
Galbusera
,
E.
,
Pastori
,
V.
,
Bigi
,
A.
et al.
(
2008
)
Study of subcellular localization and proteolysis of ataxin-3
.
Neurobiol. Dis.
30
,
190
200
132
Schwickart
,
M.
,
Huang
,
X.
,
Lill
,
J.R.
,
Liu
,
J.
,
Ferrando
,
R.
,
French
,
D.M.
et al.
(
2010
)
Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival
.
Nature
463
,
103
107
133
Rott
,
R.
,
Szargel
,
R.
,
Haskin
,
J.
,
Bandopadhyay
,
R.
,
Lees
,
A.J.
,
Shani
,
V.
et al.
(
2011
)
α-Synuclein fate is determined by USP9X-regulated monoubiquitination
.
Proc. Natl Acad. Sci. U.S.A.
108
,
18666
18671
134
Mao
,
P.
,
Manczak
,
M.
,
Calkins
,
M.J.
,
Truong
,
Q.
,
Reddy
,
T.P.
,
Reddy
,
A.P.
et al.
(
2012
)
Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension
.
Hum. Mol. Genet.
21
,
2973
2990
135
Mastroeni
,
D.
,
Nolz
,
J.
,
Khdour
,
O.M.
,
Sekar
,
S.
,
Delvaux
,
E.
,
Cuyugan
,
L.
et al.
(
2018
)
Oligomeric amyloid β preferentially targets neuronal and not glial mitochondrial-encoded mRNAs
.
Alzheimers Dement.
https://www.sciencedirect.com/science/article/pii/S1552526017338761
136
Kamat
,
C.D.
,
Gadal
,
S.
,
Mhatre
,
M.
,
Williamson
,
K.S.
,
Pye
,
Q.N.
and
Hensley
,
K.
(
2008
)
Antioxidants in central nervous system diseases: preclinical promise and translational challenges
.
J. Alzheimers Dis.
15
,
473
493
137
Kelso
,
G.F.
,
Porteous
,
C.M.
,
Coulter
,
C.V.
,
Hughes
,
G.
,
Porteous
,
W.K.
,
Ledgerwood
,
E.C.
et al.
(
2001
)
Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties
.
J. Biol. Chem.
276
,
4588
4596
138
Miquel
,
E.
,
Cassina
,
A.
,
Martínez-Palma
,
L.
,
Souza
,
J.M.
,
Bolatto
,
C.
,
Rodríguez-Bottero
,
S.
et al.
(
2014
)
Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis
.
Free Radic. Biol. Med.
70
,
204
213
139
McManus
,
M.J.
,
Murphy
,
M.P.
and
Franklin
,
J.L.
(
2011
)
The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease
.
J. Neurosci.
31
,
15703
15715
140
Ng
,
L.F.
,
Gruber
,
J.
,
Cheah
,
I.K.
,
Goo
,
C.K.
,
Cheong
,
W.F.
,
Shui
,
G.
et al.
(
2014
)
The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease
.
Free Radic. Biol. Med.
71
,
390
401
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).