Mitochondrial dysfunction in Parkinson’s disease
© The Author(s). 2016
Received: 12 April 2016
Accepted: 11 July 2016
Published: 22 July 2016
Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases. Although the cause of PD is still unclear, the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss. Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD. Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin- or genetic factor-induced PD cellular and animal models. Moreover, PINK1 and parkin, two autosomal recessive PD gene products, have important roles in mitophagy, a cellular process to clear damaged mitochondria. PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy. In this review, we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.
KeywordsParkinson’s disease Neurodegeneration Mitochondrial deficiency MPTP Mitochondrial complex I inhibitor Mitophagy
Parkinson’s disease (PD) is the second common neurodegenerative disease that affects about 1 % of adults over 60 . The motor symptoms of PD are rigidity, bradykinesia, postural instability and resting tremor, which are caused by a progressive loss of dopaminergic (DA) neurons in the substantianigra pars compacta (SNpc) . Besides loss of DA neurons in SNpc, in most familial and sporadic PD, the surviving DA neurons present cytoplasmic and neuritic inclusions named Lewy bodies (LBs) and Lewy neurites that are mainly composed of alpha-synuclein (α-syn), with other proteins in surviving DA neurons [3, 4]. Although the causative factors for DA neuronal loss are still unclear, multiple events contribute to PD pathogenesis, including protein aggregation , impairment of the ubiquitin-proteasome pathway , oxidative stress , mitochondrial dysfunction [8, 9] and neuroinflammation [10–12]. Clinically, most PD cases are sporadic; however, autosomal dominant and recessive familial forms that are resulted from mutations in PD-associated genes have been identified in the past 2 decades. Both environmental and genetic factors can induce mitochondrial dysfunction. Many of the PD-associated gene products are mitochondria-resident proteins or can be translocated to mitochondria upon stimulations. They function in either protecting or damaging mitochondria. Mutations in these genes may result in either loss or gain of function, thereby inducing mitochondrial dysfunction. Importantly, some PD-associated gene products such as PINK1 and parkin are identified as key factors involved in the induction of mitophagy, a cellular process to clear damaged mitochondria. In this review, we will discuss the role of PD-associated factors in mitochondrial dysfunction.
Evidence of mitochondrial dysfunction in sporadic PD brain and neurotoxin-induced animal model
Mitochondrial dysfunction is tightly associated with PD pathogenesis. The direct evidence of mitochondrial dysfunction in PD came from PD patient brain samples [13, 14]. In SN of PD patients, the mitochondrial complex I activity is significantly decreased [13, 14]. Moreover, a high level of mitochondrial DNA deletion was observed in SN neurons from PD patients , suggesting a role of mitochondrial dysfunction in PD. Furthermore, decreases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, a co-activator important for mitochondrial gene expressions) and PGC-1α-regulated mitochondrial genes were observed in DA neurons in PD [16, 17]. These data suggest the presence of defects in mitochondrial function and biogenesis in PD brain.
The direct linkage of mitochondrial dysfunction with PD came from the discovery of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), a neurotoxin that induces PD symptoms in drug-abused patients in 1983 . Soon, the neurotoxicity of MPTP was confirmed in primate and rodent models [19–21]. Later, the inhibitory effects of MPTP on mitochondria were identified [22–24]. Now, it is well known that the neurotoxicity of MPTP arises from its toxic metabolite 1-methyl-4-phenylpyridinium (MPP+). MPTP is converted by monoamine oxidase in astrocytes to form 1-methyl-4-phenyl-2,3-dihydropyridinium, which is rapidly converted to MPP+ . MPP+ is released from astrocytes through the organic cation transporter 3 and taken up by DA neurons through the dopamine transporter . MPP+ accumulates in mitochondria to interfere the electron transport chain by inhibiting complex I, leading to ATP depletion and reactive oxygen species (ROS) production [24, 25]. Induction of PD by the inhibition of complex I is also evidenced from studies using rotenone and paraquat, two pesticides with similar structure as MPTP, that inhibit complex I . ROS production by inhibition of complex I is a key mechanism for DA neuronal damage as DA neurons are susceptible to oxidative stress due to autoxidation of DA during catabolism . The generation of ROS induces the damage of complex I and III, and oxidation of proteins on mitochondria and in cytoplasm, leading to mitochondrial dysfunction [29, 30]. The increased oxidative stress overloads the ubiquitin-proteasomal system (UPS), resulting in the accumulation of damaged and misfolded proteins [30, 31]. Importantly, administration of complex I inhibitors induces loss of DA neurons and enables animals to develop the clinical features of PD, which has been commonly used for producing laboratory PD model mimicked sporadic PD for addressing the mechanism and exploring the therapeutics [32, 33].
Autosomal dominant PD gene products in association with mitochondrial dysfunction in PD
SNCA (PARK1) that encodes α-syn was the first gene identified to be associated with familial PD [34, 35]. α-syn is a major component of cytoplasmic inclusions (LBs) in survived DA neurons in PD brain [36, 37]. α-syn is highly enriched in presynaptic terminals . It interacts with synaptic vesicles and regulates vesicle trafficking and endocytosis . Although the neuronal toxicity of α-syn induces a wide range of cellular dysfunctions in cytoplasm, such as oxidative stress, synaptic transport, UPS impairment and autophagy dysfunction [40–42], the linkage between α-syn and mitochondrial dysfunction has been recently identified. α-syn has a mitochondrial localization, although the majority of α-syn is soluble in cytoplasm [43–45]. Most recently, α-syn is identified to be located at the mitochondria-associated membranes that connect mitochondria and endoplasmic reticulum . Overexpression of pathogenic α-syn (A53T or A30P) induces mitochondrial fragmentation, probably through inducing cleavage of dynamin-like 120 kDa protein (OPA1), a negative regulator of mitochondrial fragmentation . In transgenic mice, the pathogenic α-syn (A53T) inhibit complex I activity and induce mitochondrial degeneration . The transgenic mice present axonal degeneration, neuronal cell death and cytoplasmic inclusions positive for α-syn and nitrated α-syn, presenting pathological features as PD brains . Thus, above studies provide evidence that α-syn has effects on mitochondria, besides its indirectly influencing mitochondrial function by the induction of oxidative stress.
Mutations in LRRK2 (PARK8) are associated with autosomal dominant PD [47–49]. The frequency of mutation G2019S was reported in 5-6 % of autosomal dominant PD patients [50, 51] and even near 1 % of sporadic PD patients without a known family history of the disease . LRRK2 (leucine-rich repeat serine/threonine-protein kinase 2) is located in mitochondria, cytoplasm and nucleus . The kinase activity of LRRK2 G2019S is increased . The mitochondrial membrane potential and ATP level are decreased but mitochondrial elongation is increased in fibroblasts from PD patients harboring LRRK2 G2019S mutation . LRRK2 G2019S increases uncoupling protein level to depolarize mitochondrial membrane potential . LRRK2 interacts with dynamin-related protein 1 (DRP1), a mitochondrial fission protein . Inhibition of LRRK2 activity increases mitochondrial ROS production, DRP1 mitochondrial translocation and mitochondrial fission, suggesting an involvement of LRRK2 in the regulation of mitochondrial dynamics and oxidative stress .
Recently, the association of mitochondrial dysfunction with PD is further evidenced by the identification of a missense mutation in CHCHD2, an autosomal dominant gene associated with late-onset PD in a Japanese family  and a risk factor for sporadic PD . CHCHD2 (PARK22) encodes coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2), a protein originally identified as a transcription factor that binds to oxygen responsive element of COX4I2, a gene encoding cytochrome c oxidase (COX) subunit 4, isoform 2 that regulates cytochrome c oxidase activity . As a transcription factor, CHCHD2 transactivates the nuclear encoded COX4I2 in nucleus . However, it is also a mitochondrial intermembrane space-resident protein bound to COX and regulating COX activity . Decrease of CHCHD2 level results in decreases of COX activity and mitochondrial membrane potential, and increases of ROS production and mitochondrial fragmentation . Moreover, CHCHD2 functions in mitochondria to anti-apoptosis through its interacting with Bcl-xl to inhibit the oligomerization and mitochondrial accumulation of Bax .
Autosomal recessive PD gene products in association with mitochondrial dysfunction in PD
Three of autosomal recessive PD genes PARKIN (PARK2), PINK1 (PARK6) and DJ-1 (PARK7) are tightly associated with mitochondrial dysfunction in PD. PARKIN is the first recessive gene identified to be associated with autosomal recessive juvenile Parkinsonism in a Japanese family , just 1 year after the discovery of SNCA (α-syn). Mutations in PARKIN have been found in patients of different ethnicity and account for about half of known cases of autosomal recessive PD [64, 65]. Parkin, the PARKIN gene product, is a RING finger containing E3 ligase . A logical hypothesis is that loss of parkin function will result in the accumulation of its substrates that may be toxic for DA neurons . However, up to date, most identified substrates of parkin are not exclusively expressed in DA neurons or accumulated in PD . And the pathological LBs are absent in PD cases with PARKIN mutations. It is possible that parkin-mediated non-degradation signal also plays roles in PD as it can ubiquitinate substrate through either K63- or K48-linked ubiquitin chains . One of the parkin substrates is PARIS (Zinc finger protein 746), a major repressor of PGC-1α . Parkin ubiquitinates PARIS and regulates its expression level. In PARKIN knockout mice and PD brains, the PARIS levels are increased but PGC-1α levels are decreased . As PGC-1α is a central regulator for nuclear and mitochondrial encoded gene expressions, the mitochondrial protein expressions are decreased with the decrease of PGC-1α in PD brains . Thus, parkin may regulates mitochondrial biogenesis by its indirectly infleuencing PGC-1α level. Thus, the accumulation of PARIS in PD brain reflects loss of parkin E3 ligase activity-induced impairment of protein degradation and provides an explanation of mitochondrial dysfunction in PD.
PINK1 is a mitochondrial serine/threonine protein kinase encoded by PINK1 gene which mutations cause an autosomal recessive form of PD . PINK1 is known as a parkin upstream factor that accumulates on mitochondria upon depolarization of mitochondria and recruits parkin onto mitochondria . As a mitochondrial protein, PINK1 has multiple roles in mitochondria, including mitophagy , mitochondrial traffic , mitochondrial dynamics  and complex I activity . Depolarization of mitochondria induces PINK1/parkin to associate with Miro, a mitochondrial out membrane protein that recruits kinesin to the mitochondrial surface . PINK1 phosphorylates Miro to induce a parkin- and proteasomal-dependent degradation of Miro, thereby releasing kinesin from mitochondria, leading to an inhibition of mitochondrial motility , which may be an initial quarantining step prior to mitophagy . PINK1/parkin pathway also affects mitochondrial dynamics. Both mitochondrial fusion- and fission-proteins, such as mitofusin (Mfn) [77, 78] and DRP1 , are parkin substrates that are ubiquitinated by parkin. Phosphorylation of Mfn2 by PINK1 is required for Mfn2 interaction with and ubiquitination by parkin . PINK1 deficiency causes defect of complex I, mitochondrial depolarization and increased sensitivity to apoptotic stress . The deficiency of complex I by loss of PINK1 can be rescued by wild type PINK1, but not PD-related mutant PINK1 . Interestingly, the impaired mitochondrial respiration is presented in the striatum but not in the cerebral cortex in young PINK1 knockout mice, suggesting a specific involvement of PINK1 in DA circuitry . Recently, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 (NdufA10), a complex I subunit, was identified to be phosphorylated at S250 dependent on PINK1 . Loss of phosphorylation of S250 in NdufA10 was observed in PINK1 knockout mice . Introduction of S250D NdufA10 into PINK1 deficient cells or mutant fly restores complex I activity and membrane potential , suggesting a critical role of PINK1 in regulating complex I activity through NdufA10 phosphrylation.
DJ-1 is another PD gene which missense or deletion mutations are associated with autosomal recessive PD . DJ-1 is a multifunctional protein involved in many cellular functions , including transcriptional regulation [84, 85], anti-oxidative stress [86–88], chaperone activity  and protecting mitochondria . DJ-1 protects cells against ROS by self-oxidation at C106 . Although DJ-1 lacks mitochondrial targeting sequence and is mainly cytosolic, it can be translocated onto mitochondria against oxidative stress-induced cell death . However, pathogenic forms of DJ-1, such as L166P and M26I, are localized on mitochondria and sensitize cells to oxidative stress [82, 90]. DJ-1 binds to complex I subunits and loss of DJ-1 decreases complex I activity , suggesting that DJ-1 has impact on complex I. Interestingly, similar mitochondrial phenotype can be observed in PINK1- or DJ-1-deficient cells and mitochondrial defects in DJ-1-deficient cells can be rescued by parkin or PINK1, although PINK1/parkin pathway seems functioning in parallel to, rather than downstream of, DJ-1 pathway .
The HTRA2/OMI (PARK13) gene product HtrA2/OMI (HtrA serine peptidase 2, refer to OMI later) is a mitochondrial serine protease that was first identified as a mammalian homologue to bacterial heat shock endoprotease HtrA and named as OMI . It is released from mitochondria to cytosol to cleave XIAP in response to apoptotic stimuli, which induces apoptosis . In 2005, it was found that loss of OMI protease activity is associated with PD . mnd2 (motor neuron degeneration 2) mice which harbor protease-deficient OMI S276C mutants, and OMI-knockout mice present motor abnormalities similar to PD, with the progressive neurodegeneration in some brain regions, especially in striatum . Loss of OMI protease activity leads to mitochondrial dysfunction. The cells from mnd2 or OMI knockout mice increased susceptibility of mitochondrial membrane permeabilization, decreased mitochondrial membrane potential, and reduced mitochondrial density [96–98]. In OMI knockout mouse embryonic fibroblasts, the damage and mutation of mitochondrial DNA are increase . Interestingly, PINK1 interacts with OMI and facilitates OMI phosphorylation, which contributes to increased resistance of cells to mitochondrial stress . Moreover, in brains from PD patients with PINK1 mutaions, the phosphorylation of OMI is decreased, further suggesting that PINK1 acts on the upstream of OMI in a mitochondrial stress sensing pathway in PD.
The PLA2G6 (PARK14) gene encodes an 85-kDa calcium-independent phospholipase A2β (PLA2G6) that hydrolyses the sn-2 acyl chain of glycerophospholipids to release free fatty acids from phospholipids . PLA2G6 gene mutations cause PLA2G6-associated neurodegeneration (PLAN), including infantile neuroaxonal dystrophy  and adult-onset dystonia-parkinsonism [103, 104]. PLA2G6 is distributed in cytosol and membrane associated compartments, but mostly in mitochondria . In cells, overexpression of PLA2G6 protects cells from staurosporine-induced apoptosis through stabilizing mitochondrial membrane potential, reducing mitochondrial reactive oxygen species production . In Drosophila, loss of iPLA2-VIA, the Drosophila orthologue of PLA2G6, leads to age-dependent locomotor deficits and neurodegeneration . The flies lacking iPLA2-VIA display severe mitochondrial degeneration with decreases of mitochondrial membrane potential and ATP production . In PLA2G6 knockout mice, abnormal mitochondria with multiple morphological changes are presented in the anterior horns spinal cord . Most interestingly, in PLA2G6 knockout mice as well as PLA2G6 knockdown cells, α-syn levels are increased . The immunoreactivity of S129-site phosphorylated α-syn is strongly presented in neuronal granules which are labeled with mitochondrial outer membrane 20 kDa protein (TOM20) in PLA2G6 knockout mice , suggesting an accumulation of α-syn on damaged mitochondria. In PLAN brains, α-syn labeled small inclusions are colocalized with TOM20, which may develop to LBs , further suggesting a role of PLA2G6 in mitochondrial dysfunction and LB formation.
Mitochondrial dysfunction is a key pathological change in PD. The only way to clear the damaged mitochondria is mitophagy, a cellular process for a selective degradation of mitochondria by autophagy . The role of PINK1/parkin in mitophagy has been extensively studied after the discovery of PINK1/parkin selectively driving damaged mitochondrial degradation . The early hints of PINK1/parkin on mitochondrial homeostasis came from studies using Drosophila model [111–113]. Drosophila park null flies present prominent mitochondrial damage in muscle . Similar phenotype was observed in pink1 null flies [112, 113]. Overexprsssion of parkin in pink1 null flies rescues mitochondrial phenotype, but overexpression of PINK1 does not rescue the phenotype in parkin null flies, suggesting that parkin functions in the downstream of PINK1 [112, 113].
The role of PINK1/parkin in mitophagy was identified the study that parkin is selectively recruited to damaged mitochondria to drive mitochondrial degradation after the treatment of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler that induces mitochondrial depolarization . The recognition of mitochondria for autophagic degradation needs either mitophagy receptor or ubiquitinated protein on mitochondrial membrane. The substrates of autophagy need to be interacted with phosphatidylethanolamine-conjugated LC3 (microtubule-associated protein light chain) that is anchored on phagophore [114, 115]. Three mammalian mitophagy receptors are recently identified, including Nix (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like) , FUNDC1 (FUN14 domain-containing protein 1) , and BCL2L13 , that are located on the outer mitochondrial membrane (OMM) and able to interact directly with LC3 to induce mitophagy. The induction of mitophagy dependent on PINK1/parkin pathway is mediated by ubiquitination of mitochondria, on which the ubiquitin chains are recognized by autophagic adaptors that interact with LC3 through LC-interaction region (LIR) to link LC3-conjugated phagophore and ubiquitinated mitochondria .
Parkin ubiquitinates OMM proteins with K48- and K63-linked ubiquitin chains that play roles in parkin-dependent mitophagy . The parkin-dependently ubiquitinated mitochondria are recognized by autophagic receptor p62  or NBR1 [120, 122] for mitophagy. Interestingly, parkin induces a degradation of OMM proteins such as Mfn1, Mfn2, TOM70 and others, which is independent on autophagy but dependent on UPS [120, 123]. Degradation of OMM proteins by UPS promotes mitophagy, probably by influencing mitochondrial motility [120, 123]. Deubiquitination by deubiquitinases (DUBs) are also involved in the regulation of mitophagy. The ubiquitin-specific protease (USP) 15 decreases parkin-attached mitochondrial ubiquitin chains to interfere parkin-driven mitophagy . The mitochondrial DUB, USP30, also removes ubiquitin chains on mitochondria to block parkin-induced mitophagy . Knockdown of USP15 or USP30 improves the phenotype of parkin- or PINK1-deficient flies, suggesting a functional interaction between mitochondrial ubiquitination by parkin and deubiquitination by DUBs.
Recently, the kinase activity of PINK1 and its role in the clearance of damaged mitochondrial are well documented and reviewed [126, 127]. PINK1 phosphorylates parkin at S65 to activate parkin and to induce parkin recruitment onto mitochondria . PINK1 also pohosphorylates ubiquitin at S65, which activates parkin E3 ligase activity [129–131]. It seems that the phosphorylation of ubiquitin chains on damaged mitochondria by PINK1 is prior to and promotes parkin recruitment onto mitochondria [129, 130]. Mitochondrial damage induces accumulation of PINK1 that phosphorylates and activates parkin and ubiquitin. Meanwhile, mitochondrial damage activates serine/threonine-protein kinase TBK1, a kinas that phosphorylates autophagic adaptor optineurin, Nuclear domain 10 protein NDP52 and p62, and induces them recruitment to damaged mitochondria, leading to activation of mitophagy .
Evidence from PD patients and animal models indicate a linkage between mitochondrial dysfunction and PD pathogenesis. Environmental and genetic factors contribute to mitochondrial dysfunction in PD. One of common defects in PD patients and PD model is the deficiency of complex I. Recent findings indicate that PINK1 and parkin are involved in mitophagy. PINK1 can be accumulated on damaged mitochondria to recruit parkin onto mitochondria, resulting in ubiquitination of OMM proteins and induction of mitophagy. Loss of PINK1 or parkin leads to a failure in the clearance of damaged mitochondria, thereby inducing DA neurons susceptible to stresses. However, it is still unclear why the damaged mitochondria are not successfully cleared in sporadic PD patients or in neurotoxin- or genetic factor-induced animals that harbor wild type PINK1 and parkin. It is also unclear why loss of mitochondrial membrane potential does not induce PINK1 accumulation on mitochondria to promote mitophagy for the clearance of damaged mitochondria in vivo, although it induces mitophagy in cellular models. It is of help to identify the factors that influence PINK1 activity and accumulation on mitochondria and that affect or block PINK1 downstream factor activation in both cellular and animal models.
α-syn, alpha-synuclein; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHCHD2, coiled-coil-helix-coiled-coil-helix domain-containing protein 2; COX, cytochrome c oxidase; DA, dopaminergic; DRP1, dynamin-related protein 1; DUB, deubiquitinases; FUNDC1, FUN14 domain-containing protein 1; HtrA2/OMI, HtrA serine peptidase 2; LBs, Lewy bodies; LC3, microtubule-associated protein light chain; LIR, LC-interaction region; LRRK2, leucine-rich repeat serine/threonine-protein kinase 2; Mfn, mitofusin; mnd2, motor neuron degeneration 2; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; NDP52, Nuclear domain 10 protein; NdufA10, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10; Nix, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; OMM, outer mitochondrial membrane; OPA, dynamin-like 120 kDa protein; PARIS, zinc finger protein 746; PD, Parkinson’s disease; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PLA2G6, 85-kDa calcium-independent phospholipase A2β; PLAN, PLA2G6-associated neurodegeneration; ROS, reactive oxygen species; TOM20, mitochondrial outer membrane 20 kDa protein; UPS, ubiquitin-proteasomal system; USP ubiquitin-specific protease
This work was supported by the National Basic Research Program of China (2012CB947602), the National Natural Sciences Foundation of China (No. 31300887), Natural Science Foundation of Jiangsu Province (BK20130299), Suzhou Clinical Research Center of Neurological Disease (Szzx201503) and Jiangsu Provincial Special Program of Medical Science (BL2014042).
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HQ and WG wrote the manuscript. WG edited the manuscript. All authors read and approved the final version of this manuscript.
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- de Rijk MC, Breteler MM, Graveland GA, Ott A, Grobbee DE, van der Meche FG, Hofman A. Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology. 1995;45(12):2143–6.PubMedView ArticleGoogle Scholar
- Jankovic J. Parkinson’s disease. clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368–76.PubMedView ArticleGoogle Scholar
- Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P. Alpha-synuclein and Parkinson’s disease. FASEB J. 2004;18(6):617–26.PubMedView ArticleGoogle Scholar
- Yasuda T, Nakata Y, Mochizuki H. alpha-Synuclein and neuronal cell death. Mol Neurobiol. 2013;47(2):466–83.PubMedView ArticleGoogle Scholar
- Guerrero E, Vasudevaraju P, Hegde ML, Britton GB, Rao KS. Recent advances in alpha-synuclein functions, advanced glycation, and toxicity: implications for Parkinson’s disease. Mol Neurobiol. 2013;47(2):525–36.PubMedView ArticleGoogle Scholar
- Le W. Role of iron in UPS impairment model of Parkinson’s disease. Parkinsonism Relat Disord. 2014;20 Suppl 1:S158–161.PubMedView ArticleGoogle Scholar
- Gaki GS, Papavassiliou AG. Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson’s disease. Neruomol Med. 2014;16(2):217–30.View ArticleGoogle Scholar
- Ho PW, Ho JW, Liu HF, So DH, Tse ZH, Chan KH, Ramsden DB, Ho SL. Mitochondrial neuronal uncoupling proteins. a target for potential disease-modification in Parkinson’s disease. Transl Neurodegener. 2012;1(1):3.PubMedPubMed CentralView ArticleGoogle Scholar
- Xu R, Hu Q, Ma Q, Liu C, Wang G. The protease Omi regulates mitochondrial biogenesis through the GSK3beta/PGC-1alpha pathway. Cell Death Dis. 2014;5:e1373.PubMedPubMed CentralView ArticleGoogle Scholar
- Hu Q, Li B, Xu R, Chen D, Mu C, Fei E, Wang G. The protease Omi cleaves the mitogen-activated protein kinase kinase MEK1 to inhibit microglial activation. Sci Signal. 2012;5(238):ra61.PubMedView ArticleGoogle Scholar
- Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener. 2015;4:19.PubMedPubMed CentralView ArticleGoogle Scholar
- Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ, Zhou QB, Huang YY, Liu YJ, Wawrousek E, et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin. Nature. 2013;494(7435):90–4.PubMedView ArticleGoogle Scholar
- Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1989;1(8649):1269.PubMedView ArticleGoogle Scholar
- Bindoff LA, Birch-Machin M, Cartlidge NE, Parker Jr WD, Turnbull DM. Mitochondrial function in Parkinson’s disease. Lancet. 1989;2(8653):49.PubMedView ArticleGoogle Scholar
- Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38(5):515–7.PubMedView ArticleGoogle Scholar
- Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, et al. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med. 2010;2(52):52ra73.PubMedPubMed CentralView ArticleGoogle Scholar
- Elstner M, Morris CM, Heim K, Bender A, Mehta D, Jaros E, Klopstock T, Meitinger T, Turnbull DM, Prokisch H. Expression analysis of dopaminergic neurons in Parkinson’s disease and aging links transcriptional dysregulation of energy metabolism to cell death. Acta Neuropathol. 2011;122(1):75–86.PubMedView ArticleGoogle Scholar
- Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219(4587):979–80.PubMedView ArticleGoogle Scholar
- Kolata G. Monkey model of Parkinson’s disease. Science. 1983;220(4598):705.PubMedView ArticleGoogle Scholar
- Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A. 1983;80(14):4546–50.PubMedPubMed CentralView ArticleGoogle Scholar
- Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature. 1984;311(5985):467–9.PubMedView ArticleGoogle Scholar
- Ramsay RR, Salach JI, Dadgar J, Singer TP. Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism. Biochem Biophys Res Commun. 1986;135(1):269–75.PubMedView ArticleGoogle Scholar
- Suzuki K, Mizuno Y, Yoshida M. Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-like compounds on mitochondrial respiration. Adv Neurol. 1990;53:215–8.PubMedGoogle Scholar
- Mizuno Y, Suzuki K, Sone N. Inhibition of ATP synthesis by 1-methyl-4-phenylpyridinium ion (MPP+) in mouse brain in vitro and in vivo. Adv Neurol. 1990;53:197–200.PubMedGoogle Scholar
- Przedborski S, Tieu K, Perier C, Vila M. MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr. 2004;36(4):375–9.PubMedView ArticleGoogle Scholar
- Rappold PM, Tieu K. Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics. 2010;7(4):413–23.PubMedPubMed CentralView ArticleGoogle Scholar
- Tieu K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb Perspect Med. 2011;1(1):a009316.PubMedPubMed CentralView ArticleGoogle Scholar
- Napolitano A, Manini P, d’Ischia M. Oxidation chemistry of catecholamines and neuronal degeneration: an update. Curr Med Chem. 2011;18(12):1832–45.PubMedView ArticleGoogle Scholar
- Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5(11):863–73.PubMedView ArticleGoogle Scholar
- Abou-Sleiman PM, Muqit MM, Wood NW. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci. 2006;7(3):207–19.PubMedView ArticleGoogle Scholar
- Jenner P. Oxidative stress in Parkinson’s disease. Ann Neurol. 2003;53 Suppl 3:S26–36. discussion S36-28.PubMedView ArticleGoogle Scholar
- Hirsch EC, Hoglinger G, Rousselet E, Breidert T, Parain K, Feger J, Ruberg M, Prigent A, Cohen-Salmon C, Launay JM. Animal models of Parkinson’s disease in rodents induced by toxins: an update. J Neural Transm Suppl. 2003;65:89–100.PubMedView ArticleGoogle Scholar
- Johnson ME, Bobrovskaya L. An update on the rotenone models of Parkinson’s disease: their ability to reproduce the features of clinical disease and model gene-environment interactions. Neurotoxicology. 2015;46:101–16.PubMedView ArticleGoogle Scholar
- Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, et al. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science. 1996;274(5290):1197–9.PubMedView ArticleGoogle Scholar
- Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–7.PubMedView ArticleGoogle Scholar
- Dehay B, Decressac M, Bourdenx M, Guadagnino I, Fernagut PO, Tamburrino A, Bassil F, Meissner WG, Bezard E. Targeting alpha-synuclein: Therapeutic options. Mov Disord. 2016.
- Saleh H, Saleh A, Yao H, Cui J, Shen Y, Li R. Mini review: linkage between alpha-Synuclein protein and cognition. Transl Neurodegener. 2015;4:5.PubMedPubMed CentralView ArticleGoogle Scholar
- Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T. The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron. 1995;14(2):467–75.PubMedView ArticleGoogle Scholar
- Benskey MJ, Perez RG, Manfredsson FP. The contribution of alpha synuclein to neuronal survival and function - Implications for Parkinson’s disease. J Neurochem. 2016;137(3):331–59.PubMedView ArticleGoogle Scholar
- Choi BK, Kim JY, Cha MY, Mook-Jung I, Shin YK, Lee NK. beta-Amyloid and alpha-synuclein cooperate to block SNARE-dependent vesicle fusion. Biochemistry. 2015;54(9):1831–40.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang G, Mao Z. Chaperone-mediated autophagy: roles in neurodegeneration. Transl Neurodegener. 2014;3:20.PubMedPubMed CentralView ArticleGoogle Scholar
- Xilouri M, Brekk OR, Stefanis L. Autophagy and Alpha-Synuclein: Relevance to Parkinson’s Disease and Related Synucleopathies. Mov Disord. 2016;31(2):178–92.PubMedView ArticleGoogle Scholar
- Li WW, Yang R, Guo JC, Ren HM, Zha XL, Cheng JS, Cai DF. Localization of alpha-synuclein to mitochondria within midbrain of mice. Neuroreport. 2007;18(15):1543–6.PubMedView ArticleGoogle Scholar
- Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P. Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci. 2008;65(7–8):1272–84.PubMedView ArticleGoogle Scholar
- Guardia-Laguarta C, Area-Gomez E, Rub C, Liu Y, Magrane J, Becker D, Voos W, Schon EA, Przedborski S. alpha-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci. 2014;34(1):249–59.PubMedPubMed CentralView ArticleGoogle Scholar
- Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK. Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci. 2006;26(1):41–50.PubMedView ArticleGoogle Scholar
- Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, Obata F. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol. 2005;57(6):918–21.PubMedView ArticleGoogle Scholar
- Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M. Lopez de Munain A, Aparicio S, Gil AM, Khan N et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44(4):595–600.PubMedView ArticleGoogle Scholar
- Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–7.PubMedView ArticleGoogle Scholar
- Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet. 2005;365(9457):410–2.PubMedGoogle Scholar
- Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet. 2005;365(9457):412–5.PubMedView ArticleGoogle Scholar
- Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet. 2005;365(9457):415–6.PubMedGoogle Scholar
- West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005;102(46):16842–7.PubMedPubMed CentralView ArticleGoogle Scholar
- Mortiboys H, Johansen KK, Aasly JO, Bandmann O. Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology. 2010;75(22):2017–20.PubMedView ArticleGoogle Scholar
- Papkovskaia TD, Chau KY, Inesta-Vaquera F, Papkovsky DB, Healy DG, Nishio K, Staddon J, Duchen MR, Hardy J, Schapira AH, et al. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum Mol Genet. 2012;21(19):4201–13.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang X, Yan MH, Fujioka H, Liu J, Wilson-Delfosse A, Chen SG, Perry G, Casadesus G, Zhu X. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet. 2012;21(9):1931–44.PubMedPubMed CentralView ArticleGoogle Scholar
- Saez-Atienzar S, Bonet-Ponce L, Blesa JR, Romero FJ, Murphy MP, Jordan J, Galindo MF. The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling. Cell Death Dis. 2014;5:e1368.PubMedPubMed CentralView ArticleGoogle Scholar
- Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, et al. CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol. 2015;14(3):274–82.PubMedView ArticleGoogle Scholar
- Shi CH, Mao CY, Zhang SY, Yang J, Song B, Wu P, Zuo CT, Liu YT, Ji Y, Yang ZH, et al. CHCHD2 gene mutations in familial and sporadic Parkinson’s disease. Neurobiol Aging. 2016;38:217. e219-217 e213.PubMedView ArticleGoogle Scholar
- Aras S, Pak O, Sommer N, Finley Jr R, Huttemann M, Weissmann N, Grossman LI. Oxygen-dependent expression of cytochrome c oxidase subunit 4–2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2. Nucleic Acids Res. 2013;41(4):2255–66.PubMedPubMed CentralView ArticleGoogle Scholar
- Aras S, Bai M, Lee I, Springett R, Huttemann M, Grossman LI. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015;20:43–51.PubMedView ArticleGoogle Scholar
- Liu Y, Clegg HV, Leslie PL, Di J, Tollini LA, He Y, Kim TH, Jin A, Graves LM, Zheng J, et al. CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation. Cell Death Differ. 2015;22(6):1035–46.PubMedView ArticleGoogle Scholar
- Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392(6676):605–8.PubMedView ArticleGoogle Scholar
- Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med. 2000;342(21):1560–7.PubMedView ArticleGoogle Scholar
- Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, Meija-Santana H, Vieregge P, Jacobs H, Bressman SB, et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov Disord. 2004;19(10):1146–57.PubMedView ArticleGoogle Scholar
- Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25(3):302–5.PubMedView ArticleGoogle Scholar
- Giasson BI, Lee VM. Parkin and the molecular pathways of Parkinson’s disease. Neuron. 2001;31(6):885–8.PubMedView ArticleGoogle Scholar
- Zhang CW, Hang L, Yao TP, Lim KL. Parkin Regulation and Neurodegenerative Disorders. Front Aging Neurosci. 2015;7:248.PubMedGoogle Scholar
- Lim KL, Dawson VL, Dawson TM. Parkin-mediated lysine 63-linked polyubiquitination: a link to protein inclusions formation in Parkinson’s and other conformational diseases? Neurobiol Aging. 2006;27(4):524–9.PubMedView ArticleGoogle Scholar
- Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell. 2011;144(5):689–702.PubMedPubMed CentralView ArticleGoogle Scholar
- Handschin C. The biology of PGC-1alpha and its therapeutic potential. Trends Pharmacol Sci. 2009;30(6):322–9.PubMedView ArticleGoogle Scholar
- Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158–60.PubMedView ArticleGoogle Scholar
- Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8(1):e1000298.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell. 2011;147(4):893–906.PubMedPubMed CentralView ArticleGoogle Scholar
- Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013;23(2):64–71.PubMedView ArticleGoogle Scholar
- Morais VA, Haddad D, Craessaerts K, De Bock PJ, Swerts J, Vilain S, Aerts L, Overbergh L, Grunewald A, Seibler P, et al. PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science. 2014;344(6180):203–7.PubMedView ArticleGoogle Scholar
- Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19(24):4861–70.PubMedPubMed CentralView ArticleGoogle Scholar
- Chen Y, Dorn 2nd GW. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013;340(6131):471–5.PubMedPubMed CentralView ArticleGoogle Scholar
- Wang H, Song P, Du L, Tian W, Yue W, Liu M, Li D, Wang B, Zhu Y, Cao C, et al. Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem. 2011;286(13):11649–58.PubMedPubMed CentralView ArticleGoogle Scholar
- Morais VA, Verstreken P, Roethig A, Smet J, Snellinx A, Vanbrabant M, Haddad D, Frezza C, Mandemakers W, Vogt-Weisenhorn D, et al. Parkinson’s disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol Med. 2009;1(2):99–111.PubMedPubMed CentralView ArticleGoogle Scholar
- Gautier CA, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A. 2008;105(32):11364–9.PubMedPubMed CentralView ArticleGoogle Scholar
- Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299(5604):256–9.PubMedView ArticleGoogle Scholar
- Wang ZQ, Zhou HY, Chen SD. The role of DJ-1 in the pathogenesis of Parkinson’s disease. Neurosci Bull. 2006;22(4):232–4.PubMedGoogle Scholar
- Fan J, Ren H, Jia N, Fei E, Zhou T, Jiang P, Wu M, Wang G. DJ-1 decreases Bax expression through repressing p53 transcriptional activity. J Biol Chem. 2008;283(7):4022–30.PubMedView ArticleGoogle Scholar
- Ishikawa S, Taira T, Takahashi-Niki K, Niki T, Ariga H, Iguchi-Ariga SM. Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene. J Biol Chem. 2010;285(51):39718–31.PubMedPubMed CentralView ArticleGoogle Scholar
- Kinumi T, Kimata J, Taira T, Ariga H, Niki E. Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2004;317(3):722–8.PubMedView ArticleGoogle Scholar
- Ren H, Fu K, Wang D, Mu C, Wang G. Oxidized DJ-1 interacts with the mitochondrial protein BCL-XL. J Biol Chem. 2011;286(40):35308–17.PubMedPubMed CentralView ArticleGoogle Scholar
- Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004;5(2):213–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A. DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol. 2004;2(11):e362.PubMedPubMed CentralView ArticleGoogle Scholar
- Ren H, Fu K, Mu C, Zhen X, Wang G. L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL. Mol Neurodegener. 2012;7:40.PubMedPubMed CentralView ArticleGoogle Scholar
- Hayashi T, Ishimori C, Takahashi-Niki K, Taira T, Kim YC, Maita H, Maita C, Ariga H, Iguchi-Ariga SM. DJ-1 binds to mitochondrial complex I and maintains its activity. Biochem Biophys Res Commun. 2009;390(3):667–72.PubMedView ArticleGoogle Scholar
- Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A, Miller D, Maric D, Cedazo-Minguez A, Cookson MR. DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet. 2011;20(1):40–50.PubMedView ArticleGoogle Scholar
- Faccio L, Fusco C, Chen A, Martinotti S, Bonventre JV, Zervos AS. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J Biol Chem. 2000;275(4):2581–8.PubMedView ArticleGoogle Scholar
- Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001;8(3):613–21.PubMedView ArticleGoogle Scholar
- Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet. 2005;14(15):2099–111.PubMedView ArticleGoogle Scholar
- Jones JM, Datta P, Srinivasula SM, Ji W, Gupta S, Zhang Z, Davies E, Hajnoczky G, Saunders TL, Van Keuren ML, et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature. 2003;425(6959):721–7.PubMedView ArticleGoogle Scholar
- Rathke-Hartlieb S, Schlomann U, Heimann P, Meisler MH, Jockusch H, Bartsch JW. Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. Exp Neurol. 2002;175(1):87–97.PubMedView ArticleGoogle Scholar
- Kang S, Louboutin JP, Datta P, Landel CP, Martinez D, Zervos AS, Strayer DS, Fernandes-Alnemri T, Alnemri ES. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death Differ. 2013;20(2):259–69.PubMedView ArticleGoogle Scholar
- Goo HG, Jung MK, Han SS, Rhim H, Kang S. HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. Biochim Biophys Acta. 2013;1833(8):1866–75.PubMedView ArticleGoogle Scholar
- Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, Harvey K, Deas E, Harvey RJ, McDonald N, et al. The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol. 2007;9(11):1243–52.PubMedView ArticleGoogle Scholar
- Ma Z, Turk J. The molecular biology of the group VIA Ca2 + −independent phospholipase A2. Prog Nucleic Acid Res Mol Biol. 2001;67:1–33.PubMedView ArticleGoogle Scholar
- Khateeb S, Flusser H, Ofir R, Shelef I, Narkis G, Vardi G, Shorer Z, Levy R, Galil A, Elbedour K, et al. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet. 2006;79(5):942–8.PubMedPubMed CentralView ArticleGoogle Scholar
- Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW, Hardy J, Houlden H, Singleton A, Schneider SA. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol. 2009;65(1):19–23.PubMedView ArticleGoogle Scholar
- Sina F, Shojaee S, Elahi E, Paisan-Ruiz C. R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family. Eur J Neurol. 2009;16(1):101–4.PubMedView ArticleGoogle Scholar
- Seleznev K, Zhao C, Zhang XH, Song K, Ma ZA. Calcium-independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine. J Biol Chem. 2006;281(31):22275–88.PubMedPubMed CentralView ArticleGoogle Scholar
- Kinghorn KJ, Castillo-Quan JI, Bartolome F, Angelova PR, Li L, Pope S, Cocheme HM, Khan S, Asghari S, Bhatia KP, et al. Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain. 2015;138(Pt 7):1801–16.PubMedPubMed CentralView ArticleGoogle Scholar
- Beck G, Sugiura Y, Shinzawa K, Kato S, Setou M, Tsujimoto Y, Sakoda S, Sumi-Akamaru H. Neuroaxonal dystrophy in calcium-independent phospholipase A2beta deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes. J Neurosci. 2011;31(31):11411–20.PubMedView ArticleGoogle Scholar
- Sumi-Akamaru H, Beck G, Shinzawa K, Kato S, Riku Y, Yoshida M, Fujimura H, Tsujimoto Y, Sakoda S, Mochizuki H. High expression of alpha-synuclein in damaged mitochondria with PLA2G6 dysfunction. Acta Neuropathol Commun. 2016;4:27.PubMedPubMed CentralView ArticleGoogle Scholar
- Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462(2):245–53.PubMedPubMed CentralView ArticleGoogle Scholar
- Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183(5):795–803.PubMedPubMed CentralView ArticleGoogle Scholar
- Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003;100(7):4078–83.PubMedPubMed CentralView ArticleGoogle Scholar
- Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006;441(7097):1157–61.PubMedView ArticleGoogle Scholar
- Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441(7097):1162–6.PubMedView ArticleGoogle Scholar
- Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci. 2004;117(Pt 13):2805–12.PubMedView ArticleGoogle Scholar
- Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1–222.PubMedView ArticleGoogle Scholar
- Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Lohr F, Popovic D, Occhipinti A, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010;11(1):45–51.PubMedView ArticleGoogle Scholar
- Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. 2012;14(2):177–85.PubMedView ArticleGoogle Scholar
- Otsu K, Murakawa T, Yamaguchi O. BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32. Autophagy. 2015;11(10):1932–3.PubMedView ArticleGoogle Scholar
- Shaid S, Brandts CH, Serve H, Dikic I. Ubiquitination and selective autophagy. Cell Death Differ. 2013;20(1):21–30.PubMedView ArticleGoogle Scholar
- Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL, Hess S, Chan DC. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet. 2011;20(9):1726–37.PubMedPubMed CentralView ArticleGoogle Scholar
- Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119–31.PubMedView ArticleGoogle Scholar
- Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015;24(9):2528–38.PubMedView ArticleGoogle Scholar
- Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol. 2010;191(7):1367–80.PubMedPubMed CentralView ArticleGoogle Scholar
- Cornelissen T, Haddad D, Wauters F, Van Humbeeck C, Mandemakers W, Koentjoro B, Sue C, Gevaert K, De Strooper B, Verstreken P, et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet. 2014;23(19):5227–42.PubMedView ArticleGoogle Scholar
- Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS, Sheng M. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014;510(7505):370–5.PubMedGoogle Scholar
- Chin LS, Li L. Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment. Transl Neurodegener. 2016;5:1.PubMedPubMed CentralView ArticleGoogle Scholar
- Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron. 2015;85(2):257–73.PubMedPubMed CentralView ArticleGoogle Scholar
- Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H, Macartney TJ, Deak M, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2(5):120080.PubMedPubMed CentralView ArticleGoogle Scholar
- Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205(2):143–53.PubMedPubMed CentralView ArticleGoogle Scholar
- Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014;460(1):127–39.PubMedPubMed CentralView ArticleGoogle Scholar
- Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510(7503):162–6.PubMedGoogle Scholar
- Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW. The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy. Mol Cell. 2015;60(1):7–20.PubMedView ArticleGoogle Scholar