Mitochondria play key roles in the cellular metabolism of lipids and iron as well as in cell death signaling. Mitochondrial dysregulation produces reactive oxygen species (ROS), which results in oxidative stress. Moreover, the accumulation of damaged mitochondria leads to cell death and tissue dysfunction. Mitochondrial maintenance involves mitophagy, a selective autophagy process that removes abnormal mitochondria. Parkinson’s disease (PD) is a movement disorder caused by the specific loss of dopaminergic neurons in the substantia nigra of the midbrain. Two genes implicated in PD, PINK1 and Parkin, regulate mitophagy in cultured cells. Reduction of the ΔΨm leads to activation of PINK1, which stimulates the recruitment of Parkin to the mitochondrial outer membrane of damaged mitochondria and activates Parkin’s ubiquitin-ligase activity. Activated mitochondrial Parkin leads to the ubiquitination of mitochondrial proteins and subsequent mitophagy. This elaborate molecular mechanism was recently uncovered and the findings demonstrate the physiological and pathological roles of the PINK1-Parkin pathway. Here, we review these key findings on the molecular mechanism and ideas relevant to neurodegeneration caused by dysregulation of the PINK1-Parkin pathway.
- Dopaminergic neurons
- Parkinson’s disease
- protein kinase
- ubiquitin ligase
In eukaryotic cells, mitochondria are highly efficient power-generating systems that perform aerobic respiration. Injured mitochondria leak ROS, resulting in oxidative stress and reduction of energy supply; this dysfunction eventually leads to cell death. Therefore, appropriate regulation of mitochondria is critical for vital activity and anti-aging. Mitochondrial dysregulation has indeed been implicated in various human diseases, including cancer, diabetes, myopathy, and a variety of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Huntington’s disease, neuropathy, and Parkinson’s disease (PD). PD is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the midbrain. The motor symptoms of PD include tremor, rigidity, slowness of movement, and difficulty with ambulation. Although familial forms of PD are relatively rare cases, the identification of genes responsible for PD enables a better understanding of the molecular mechanisms underlying neurodegeneration.
The selective degradation of mitochondria via an autophagic process was originally reported as mitophagy by J.J. Lamasters et al. . In yeast, loss of the
2. Mitochondrial segregation and mitophagy
Damaged mitochondria are selectively segregated and degraded by mitophagy . Mitochondrial morphology is maintained by mitochondrial fusion and fission. Mitofusin (Mfn) regulates or mediates mitochondrial fusion whereas Drp1 and Fis1 promote mitochondrial fission in mammals as well as in yeast . Inhibition of Drp1 or Fis1 activity results in the suppression of mitophagy and the accumulation of oxidized mitochondrial proteins, leading to reduced respiration and impaired insulin secretion . Orthologs of
3. Parkin E3 ligase and ubiquitination
E3 ubiquitin ligases are roughly divided into two groups: RING finger-type E3 ligases and homologous to the E6AP carboxyl terminus (HECT)-type E3 ligases. HECT-type E3 ligases form a thioester intermediate between ubiquitin and a catalytic cysteine residue before transferring ubiquitin from E2 to a substrate. By contrast, RING finger-type E3 ligases mediate the direct transfer of ubiquitin from E2 to the substrate. Parkin, which was formerly classified as a RING finger-type E3 ligase, is now categorized as a HECT-RING hybrid E3-ligase [25, 26]. To activate Parkin, a ubiquitin-charged E2 associates with Parkin RING1 and ubiquitin is transferred from E2 to Cys431 in the RING2 domain of Parkin to form the HECT-like thioester intermediate [25–27]. Similar molecular behaviors were observed in other RBR proteins such as HHARI, and proteins containing a RBR domain are thought to be HECT-RING hybrid E3-ligases [25, 26].
It has been reported that Parkin binds to four tandem-repeated mitochondrial ubiquitin chains, which mimic Lys63-linked polyubiquitin chains only when PINK1 is activated . Subsequent reports have revealed that PINK1 phosphorylates mitochondrial polyubiquitin, resulting in Parkin activation and mitochondrial relocation (Figure 3) [41, 47]. While PINK1 phosphorylates both monoubiquitin and polyubiquitin, including Lys48- and Lys63-linked polyubiquitin chains, activated Parkin preferentially associates with Lys63-linked phosphorylated polyubiquitin chains on mitochondria . Lys48-linked polyubiquitin chains are generally utilized as signals for proteasomal degradation , whereas Lys63-linked ubiquitin chains were first identified in yeast as atypical ubiquitin chains that respond to stress . A variety of functions of Lys63-linked polyubiquitin chains were subsequently characterized, including the regulation of kinase activity, DNA damage response, signal transduction scaffolding, vesicular trafficking, and endocytosis . Thus, the formation of Lys63-linked ubiquitin chains during mitophagy might have a critical role beyond Parkin recruitment .
Several reports have demonstrated that Parkin-interacting E2 enzymes mediate the ubiquitination reaction of Parkin. UBE2N is related to Parkin-mediated Lys63-linked ubiquitination [51, 52], whereas UBE2N, UBE2L3, and UBE2D2/3 synergistically contribute to Parkin-mediated mitophagy . Knockdown of UBE2N, UBE2L3, or UBE2D2/3 but not UBE2A, UBE2S, or UBE2T significantly reduces autophagic clearance of depolarized mitochondria or Parkin E3 activity [53, 54]. However, recent reports indicate that the linkage property of polyubiquitination depends on Parkin itself rather than involved E2s , and that atypical Lys6- and Lys11-mediated polyubiquitination chains are also generated by Parkin and contribute to mitophagy [47, 55].
Deubiquitinating enzymes (DUBs) are also involved in PINK1-Parkin-mediated mitophagy. Because USP30 preferentially removes Lys6- and Lys11-linked ubiquitin chains generated by Parkin on damaged mitochondria, USP30 knockdown rescues the defective mitophagy caused by pathogenic mutations in Parkin [55, 56]. Moreover, knockdown of USP30 improves mitochondrial morphology in
PINK1 and Parkin promote selective turnover of the respiratory chain complex in
4. Regulators of PINK1
PINK1 stability is regulated by mitochondrial outer and inner membrane proteins, and upregulation of these proteins triggers PINK1 activation through dimerization and autophosphorylation (Figure 4) [62, 63]. PINK1 interacts with the translocase of the outer membrane (TOM) complex and is imported to the mitochondrial inner membrane [64, 65]. Under steady-state conditions, endogenous PINK1 is constitutively and rapidly degraded by the E3 ubiquitin ligases UBR1, UBR2, and UBR4 through the N-end rule pathway . The PINK1 precursor is inserted into the mitochondrial inner membrane, where PINK1 is subjected to processing by mitochondrial proteases. The rhomboid family protease PARL, which is localized at the mitochondrial inner membrane, cleaves PINK1 at Ala103 in a ΔΨm-dependent manner [66–70]. Cleaved PINK1 is released to the cytosol or mitochondrial intermembrane space . However, the molecular mechanism of its reverse transport from the mitochondria to the cytosol remains unclear. The mitochondrial processing peptidase and hetero dimeric matrix proteases m-AAA and ClpXP are also involved in PINK1 cleavage . These reports indicate that mitochondrial inner and matrix proteases coordinately regulate PINK1 stability in a ΔΨm-dependent manner.
Lefebvre et al. identified ATPase inhibitory factor 1 (ATPIF1/IF1) as essential for Parkin translocation from cytosol to mitochondria and for mitophagy in cultured cells . ATPF1 inhibits the reversal of F1Fo-ATP synthase and promotes the reduction in ΔΨm, resulting in the accumulation of PINK1 and the subsequent activation of mitophagy .
The master transcriptional factor for lipogenesis, sterol regulatory element binding transcription factor 1 (SREBF1), promotes Parkin translocation and mitophagy . Although SREBF1 knockdown inhibits carbonyl cyanidem-chlorophenylhydrazone (CCCP)-induced PINK1 stabilization and Parkin translocation, the addition of excess amounts of cholesterol rescues these deficits, suggesting that SREBF1-dependent lipid synthesis may be a key factor in PINK1 stabilization .
5. Regulators of Parkin and mitophagy
Parkin-mediated ubiquitination of mitochondrial proteins initiates proteasomal and autophagic degradation, which involves a variety of regulators and ubiquitin- and/or LC3-binding proteins (Figure 5). The ubiquitin- and LC3-binding protein p62/SQSTM1 is required for Parkin-induced clustering of depolarized mitochondria to the perinuclear region [33, 77, 78]. Neighbor of BRCA1 gene 1 (NBR1), a functional homolog of p62, is also a ubiquitin-binding protein and is recruited to depolarized mitochondria in a PINK1-Parkin-dependent manner . p62 and NBR1 expression levels coordinately change, suggesting a positive mutual regulatory relationship between p62 and NBR1 at least during viral infection . Optineurin, an autophagy receptor that binds to ubiquitinated mitochondria via ubiquitin-binding domains, is translocated to damaged mitochondria in a Parkin-dependent manner and recruits LC3 to induce mitochondrial degradation via autophagosomes . However, optineurin and p62 are independently recruited to damaged mitochondria . Tank-binding kinase 1 (TBK1) phosphorylates optineurin and p62, which enhances their binding affinity to LC3 and ubiquitin [82, 83]. Although TBK1 is activated downstream of Toll-like receptor 3 (TLR3) and the TLR4 signaling pathway, it is unknown which signaling event activates TBK1 during mitophagy . Ambra1, an autophagy-promoting protein, is not required for Parkin translocation to depolarized mitochondria . However, the interaction of Parkin with Ambra1 is potentiated during prolonged mitochondrial depolarization, resulting in the activation of the autophagy-associated class III phosphatidylinositol 3-kinase (PI3K) complex in mitochondria and their selective autophagic clearance .
Recent genome-wide RNAi screens have also identified several regulators of PINK1 and Parkin. Hasson et al. found that TOMM7, one of the TOM components, is necessary for the accumulation of PINK1 and Parkin on damaged mitochondria and chaperone proteins, HSPA1L and BAG4, have mutually opposing roles in Parkin translocation . TOMM7 knockout causes impaired PINK1 import into mitochondria by inhibiting the interaction of PINK1 with the TOM complex. Moreover, a mitochondrial E3 ligase SIAH3 inhibits PINK1 accumulation probably through ubiquitination-proteasome-dependent degradation, resulting in decreased Parkin translocation . Another chaperone protein, Hsp72, rapidly translocates to depolarized mitochondria prior to Parkin recruitment and interacts with both Parkin and Mfn2 only after specific mitochondrial insults . Myotubes in both Hsp72 knockout mice and Parkin knockout mice exhibit increased insulin resistance and reduced maximal respiration . Furthermore, myotubes in Hsp72 knockout mice exhibit impaired CCCP-induced Mfn2 degradation and Parkin-mediated LC3-II accumulation, suggesting that Hsp72 is a positive regulator of Parkin in mitophagy .
McCoy et al. revealed that knockdown of hexokinase (HK)1 and HK2 inhibits Parkin translocation from the cytosol to the mitochondria . Inhibition of AKT signaling attenuates Parkin recruitment to mitochondria and suppresses the translocation of HK2 to mitochondria, suggesting that AKT promotes Parkin relocation .
6. Mitochondrial motility regulated by PINK1-Parkin
PINK1 and Parkin regulate mitochondrial motility in addition to mitophagy, which appears to be particularly important for neuronal function. In neurons, mitochondria are transported from the cell body to nerve terminals. Mitochondrial Rho GTPase 1 (Miro1) regulates the microtubule-dependent transport of mitochondria along with Milton, kinesin, and dynein . In
7. Mitochondria and PD
Respiratory complex I or NADH dehydrogenase activity is significantly reduced in the substantia nigra of PD patients [94–96], implying that selective dysregulation of complex I activity is a key component of PD pathogenesis. The fact that neurotoxin 1-methyl-4-phenylpyridinium (MPP+) causes selective loss of dopaminergic neurons, which causes symptoms similar to Parkinsonism, reinforces this idea . MPP+ is produced by the monoamine oxidase (MAO)-mediated oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and is imported into dopaminergic neurons via dopamine reuptake systems [98, 99]. In dopaminergic neurons, MPP+ is concentrated in the mitochondrial matrix and binds to NADH dehydrogenase, resulting in the inhibition of OXPHOS, ATP depletion, and dopaminergic neuron death .
In addition to PINK1 and Parkin, other genes that have been implicated in PD are also related to mitochondrial homeostasis. Mutations in DJ-1 are associated with early-onset PD [101, 102]. DJ-1 alleviates oxidative stress through its antioxidant activity and functions as a redox-sensitive molecular chaperone . Loss of DJ-1 leads to abnormal mitochondrial phenotypes, including reduced ΔΨm, increased fragmentation and accumulation of autophagic markers . CHCHD2 was isolated as a novel PD-associated gene  and is thought to regulate OXPHOS in mitochondria . PINK1 inhibition causes decreased dopaminergic neuron viability in
Two genes implicated in PD,
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392(6676):605–8.
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;304(5674):1158–60.
Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 2007;462(2):245–53.
Nowikovsky K, Reipert S, Devenish RJ, Schweyen RJ. Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy. Cell Death Differ 2007;14(9):1647–56.
Mortensen M, Ferguson DJ, Simon AK. Mitochondrial clearance by autophagy in developing erythrocytes: clearly important, but just how much so? Cell Cycle 2010;9(10):1901–6.
Sato M, Sato K. Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegansembryos. Science 2011;334(6059):1141–4.
Al Rawi S, Louvet-Vallee S, Djeddi A, Sachse M, Culetto E, Hajjar C, et al. Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission. Science 2011;334(6059):1144–7.
Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin. J Cell Sci 2001;114(Pt 5):867–74.
Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008;27(2):433–46.
Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Nat Acad Sci USA 2003;100(7):4078–83.
Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 2006;441(7097):1157–61.
Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 2006;441(7097):1162–6.
Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang JW, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Nat Acad Sci USA 2006;103(28):10793–98.
Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Nat Acad Sci USA 2008;105(5):1638–43.
Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vogel H, et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Nat Acad Sci USA 2008;105(19):7070–5.
Deng H, Dodson MW, Huang H, Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Nat Acad Sci USA 2008;105(38):14503–8.
Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One 2010;5(4):e10054.
Ziviani E, Tao RN, Whitworth AJ. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Nat Acad Sci USA 2010;107(11):5018–23.
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.
Glauser L, Sonnay S, Stafa K, Moore DJ. Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem 2011;118(4):636–45.
Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 2010;191(7):1367–80.
Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 2000;275(46):35661–4.
Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000;25(3):302–5.
Hristova VA, Beasley SA, Rylett RJ, Shaw GS. Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J Biol Chem 2009;284(22):14978–86.
Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 2011;474(7349):105–8.
Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L, et al. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat Commun 2013;4:1982.
Wauer T, Komander D. Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J 2013;32(15):2099–112.
Takatori S, Ito G, Iwatsubo T. Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett 2008;430(1):13–7.
Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 2010;8(1):e1000298.
Yamano K, Youle RJ. PINK1 is degraded through the N-end rule pathway. Autophagy 2013;9(11):1758–69.
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.
Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Nat Acad Sci USA 2010;107(1):378–83.
Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010;12(2):119–31.
Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010;189(2):211–21.
Kawajiri S, Saiki S, Sato S, Sato F, Hatano T, Eguchi H, et al. PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy. FEBS Lett 2010;584(6):1073–9.
Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ, Shaw GS, et al. Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J 2011;30(14):2853–67.
Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, et al. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep 2012;2:1002.
Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, 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.
Iguchi M, Kujuro Y, Okatsu K, Koyano F, Kosako H, Kimura M, et al. Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation. J Biol Chem 2013;288(30):22019–32.
Kazlauskaite A, Kelly V, Johnson C, Baillie C, Hastie CJ, Peggie M, et al. Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate-based assay of Parkin E3 ligase activity. Open Biol 2014;4:130213.
Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, et al. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet 2014;10(12):e1004861.
Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y. PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. PLoS Genet 2014;10(6):e1004391.
Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 2014;205(2):143–53.
Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J 2014;460(1):127–39.
Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 2014;510(7503):162–6.
Zheng X, Hunter T. Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism. Cell Res 2013;23(7):886–97.
Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO, et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 2014;56(3):360–75.
Thrower JS, Hoffman L, Rechsteiner M, Pickart CM. Recognition of the polyubiquitin proteolytic signal. EMBO J 2000;19(1):94–102.
Arnason T, Ellison MJ. Stress resistance in Saccharomyces cerevisiaeis strongly correlated with assembly of a novel type of multiubiquitin chain. Mol Cell Biol 1994;14(12):7876–83.
Erpapazoglou Z, Walker O, Haguenauer-Tsapis R. Versatile roles of k63-linked ubiquitin chains in trafficking. Cells 2014;3(4):1027–88.
Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y. Lysine 63-linked polyubiquitination is dispensable for Parkin-mediated mitophagy. J Biol Chem 2014;289(48):33131–6.
Lim GG, Chew KC, Ng XH, Henry-Basil A, Sim RW, Tan JM, et al. Proteasome inhibition promotes Parkin-Ubc13 interaction and lysine 63-linked ubiquitination. PLoS One 2013;8(9):e73235.
Geisler S, Vollmer S, Golombek S, Kahle PJ. The ubiquitin-conjugating enzymes UBE2N, UBE2L3 and UBE2D2/3 are essential for Parkin-dependent mitophagy. J Cell Sci 2014;127(Pt 15):3280–93.
Fiesel FC, Moussaud-Lamodiere EL, Ando M, Springer W. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci 2014;127(Pt 16):3488–504.
Cunningham CN, Baughman JM, Phu L, Tea JS, Yu C, Coons M, et al. USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria. Nat Cell Biol 2015;17(2):160–9.
Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 2014;510(7505):370–5.
Durcan TM, Tang MY, Perusse JR, Dashti EA, Aguileta MA, McLelland GL, et al. USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J 2014;33(21):2473–91.
Cornelissen T, Haddad D, Wauters F, Van Humbeeck C, Mandemakers W, Koentjoro B, et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet 2014;23(19):5227–42.
Vincow ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP, MacCoss MJ, et al. The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc Nat Acad Sci USA 2013;110(16):6400–5.
Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 2013;496(7445):372–6.
Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 2013;501(7468):512–6.
Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, Tani N, et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat Commun 2012;3:1016.
Okatsu K, Uno M, Koyano F, Go E, Kimura M, Oka T, et al. A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment. J Biol Chem 2013;288(51):36372–84.
Lazarou M, Jin SM, Kane LA, Youle RJ. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell 2012;22(2):320–33.
Kato H, Lu Q, Rapaport D, Kozjak-Pavlovic V. Tom70 is essential for PINK1 import into mitochondria. PLoS One 2013;8(3):e58435.
Whitworth AJ, Lee JR, Ho VM, Flick R, Chowdhury R, McQuibban GA. Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin. Dis Model Mech 2008;1(2–3):168–74; discussion 173.
Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 2010;191(5):933–42.
Deas E, Plun-Favreau H, Gandhi S, Desmond H, Kjaer S, Loh SH, et al. PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 2011;20(5):867–79.
Shi G, Lee JR, Grimes DA, Racacho L, Ye D, Yang H, et al. Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease. Hum Mol Genet 2011;20(10):1966–74.
Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK. The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 2011;117(5):856–67.
Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, et al. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 2012;13(4):378–85.
Imai Y, Kanao T, Sawada T, Kobayashi Y, Moriwaki Y, Ishida Y, et al. The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. PLoS Genet 2010;6(12):e1001229.
Lu W, Karuppagounder SS, Springer DA, Allen MD, Zheng L, Chao B, et al. Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder. Nat Commun 2014;5:4930.
Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 2012;148(1–2):228–43.
Lefebvre V, Du Q, Baird S, Ng AC, Nascimento M, Campanella M, et al. Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy. Autophagy 2013;9(11):1770–9.
Ivatt RM, Sanchez-Martinez A, Godena VK, Brown S, Ziviani E, Whitworth AJ. Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc Nat Acad Sci USA 2014;111(23):8494–9.
Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 2010;15(8):887–900.
Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 2010;6(8):1090–106.
Hollville E, Carroll RG, Cullen SP, Martin SJ. Bcl-2 family proteins participate in mitochondrial quality control by regulating Parkin/PINK1-dependent mitophagy. Mol Cell 2014;55(3):451–66.
Shi J, Fung G, Piesik P, Zhang J, Luo H. Dominant-negative function of the C-terminal fragments of NBR1 and SQSTM1 generated during enteroviral infection. Cell Death Differ 2014;21(9):1432–41.
Wong YC, Holzbaur EL. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Nat Acad Sci USA 2014;111(42):E4439–48.
Pilli M, Arko-Mensah J, Ponpuak M, Roberts E, Master S, Mandell MA, et al. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 2012;37(2):223–34.
Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 2011;333(6039):228–33.
McCoy CE, Carpenter S, Palsson-McDermott EM, Gearing LJ, O'Neill LA. Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation. J Biol Chem 2008;283(21):14277–85.
Van Humbeeck C, Cornelissen T, Hofkens H, Mandemakers W, Gevaert K, De Strooper B, et al. Parkin interacts with Ambra1 to induce mitophagy. J Neurosci 2011;31(28):10249–61.
Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, et al. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 2013;504(7479):291–5.
Drew BG, Ribas V, Le JA, Henstridge DC, Phun J, Zhou Z, et al. HSP72 is a mitochondrial stress sensor critical for Parkin action, oxidative metabolism, and insulin sensitivity in skeletal muscle. Diabetes 2014;63(5):1488–505.
McCoy MK, Kaganovich A, Rudenko IN, Ding J, Cookson MR. Hexokinase activity is required for recruitment of parkin to depolarized mitochondria. Hum Mol Genet 2014;23(1):145–56.
Saxton WM, Hollenbeck PJ. The axonal transport of mitochondria. J Cell Sci 2012;125(Pt 9):2095–104.
Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P, et al. Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet 2012;8(3):e1002537.
Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell. 2011;147(4):893–906.
Birsa N, Norkett R, Wauer T, Mevissen TE, Wu HC, Foltynie T, et al. Lysine 27 ubiquitination of the mitochondrial transport protein Miro is dependent on serine 65 of the Parkin ubiquitin ligase. J Biol Chem 2014;289(21):14569–82.
Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci 2010;30(12):4232–40.
Parker WD, Jr., Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 1989;26(6):719–23.
Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 1990;54(3):823–7.
Mizuno Y, Suzuki K, Ohta S. Postmortem changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson's disease. J Neurol Sci 1990;96(1):49–57.
Langston JW, Langston EB, Irwin I. MPTP-induced parkinsonism in human and non-human primates--clinical and experimental aspects. Acta Neurol Scand Suppl 1984;100:49–54.
Trevor AJ, Singer TP, Ramsay RR, Castagnoli N, Jr. Processing of MPTP by monoamine oxidases: implications for molecular toxicology. J Neural Transm Suppl 1987;23:73–89.
Kopin IJ, Markey SP. MPTP toxicity: implications for research in Parkinson's disease. Annu Rev Neurosci 1988;11:81–96.
Singer TP, Ramsay RR, McKeown K, Trevor A, Castagnoli NE, Jr. Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology 1988;49(1):17–23.
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299(5604):256–9.
Tao X, Tong L. Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease. J Biol Chem 2003;278(33):31372–9.
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.
McCoy MK, Cookson MR. DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy. 2011;7(5):531–2.
Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, 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.
Baughman JM, Nilsson R, Gohil VM, Arlow DH, Gauhar Z, Mootha VK. A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis. PLoS Genet 2009;5(8):e1000590.
Burman JL, Yu S, Poole AC, Decal RB, Pallanck L. Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants. Proc Nat Acad Sci USA 2012;109(26):10438–43.
Westlund KN, Denney RM, Rose RM, Abell CW. Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem. Neuroscience 1988;25(2):439–56.