Pink1/Parkin介导的线粒体自噬分子机制
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摘要
线粒体自噬作为一种选择性清除受损线粒体的特异性自噬类型,是细胞内线粒体的质量控制体系,其活性受多种途径调控。近年来,关于线粒体自噬的调控及其对生理、病理方面的影响受到众多研究者的关注,并获得了显著的研究成果。研究表明,人PTEN诱导激酶1(PTEN induced putative kinase 1,Pink1)/Parkin通路调控线粒体动力学过程,并介导受损线粒体的自噬性清除。PINK1/PARK2基因缺失或突变是神经退行性疾病的重要发病机制之一,其功能异常也与多种肿瘤的发生有关。该综述主要介绍了Pink1/Parkin蛋白质的生化特性、介导线粒体自噬发生的分子机制及其对细胞生物学进程的影响。
Mitophagy, the selective degradation of damaged mitochondria via autophagy dependent manner, is an important mitochondrial quality control system and regulated by a variety of pathways. In recent years, the regulation of mitophagy and its effects on physiology and pathology have been attracted increasing attention and obtained remarkable progress. The present evidence indicates that Pink1/Parkin pathway regulates mitochondrial dynamics and mediates the removal of damaged mitochondria via autophagy. Defects in PINK1/PARK2 are the main cause of Parkinson's disease. In addition, the dysfunction of Pink1/Parkin may have a role in the development of cancer. This review discribes the biochemical characteristics of Pink1/Parkin, highlights the molecular mechanism of mitopagy and its impact on the cellular processes.
Mitophagy, the selective degradation of damaged mitochondria via autophagy dependent manner, is an important mitochondrial quality control system and regulated by a variety of pathways. In recent years, the regulation of mitophagy and its effects on physiology and pathology have been attracted increasing attention and obtained remarkable progress. The present evidence indicates that Pink1/Parkin pathway regulates mitochondrial dynamics and mediates the removal of damaged mitochondria via autophagy. Defects in PINK1/PARK2 are the main cause of Parkinson's disease. In addition, the dysfunction of Pink1/Parkin may have a role in the development of cancer. This review discribes the biochemical characteristics of Pink1/Parkin, highlights the molecular mechanism of mitopagy and its impact on the cellular processes.
引文
1 Mc Williams TG,Muqit MM.PINK1 and Parkin:Emerging themes in mitochondrial homeostasis.Curr Opin Cell Biol 2017;45:83-91.
2 Dengjel J,Abeliovich H.Roles of mitophagy in cellular physiology and development.Cell Tissue Res 2017;367(1):95-109.
3 Lill CM.Genetics of Parkinson’s disease.Mol Cell Probes 2016;30(6):386-96.
4 Gispert S,Ricciardi F,Kurz A,Azizov M,Hoepken HH,Becker D,et al.Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.PLo S One 2009;4(6):e5777.
5 Matsui H,Gavinio R,Asano T,Uemura N,Ito H,Taniguchi Y,et al.PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates.Hum Mol Genet 2013;22(12):2423-34.
6 Triplett JC,Zhang Z,Sultana R,Cai J,Klein JB,Bueler H,et al.Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice:Insights into mechanisms of familial Parkinson’s disease.J Neurochem 2015;133(5):750-65.
7 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.
8 Morgante F,Fasano A,Ginevrino M,Petrucci S,Ricciardi L,Bove F,et al.Impulsive-compulsive behaviors in parkinassociated Parkinson disease.Neurology 2016;87(14):1436-41.
9 Bernardini JP,Lazarou M,Dewson G.Parkin and mitophagy in cancer.Oncogene 2017;36(10):1315-27.
10 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.
11 Callegari S,Oeljeklaus S,Warscheid B,Dennerlein S,Thumm M,Rehling P,et al.Phospho-ubiquitin-PARK2 complex as a marker for mitophagy defects.Autophagy 2017;13(1):201-11.
12 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.
13 Kane LA,Lazarou M,Fogel AI,Li Y,Yamano K,Sarraf SA,et al.PINK1 phosphorylates ubiquitin to activate Parkin E3ubiquitin ligase activity.J Cell Biol 2014;205(2):143-53.
14 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.
15 Wauer T,Simicek M,Schubert A,Komander D.Mechanism of phospho-ubiquitin-induced PARKIN activation.Nature 2015;524(7565):370-4.
16 Schulz C,Schendzielorz A,Rehling P.Unlocking the presequence import pathway.Trends Cell Biol 2015;25(5):265-75.
17 Aerts L,Craessaerts K,De Strooper B,Morais VA.PINK1 kinase catalytic activity is regulated by phosphorylation on serines 228and 402.J Biol Chem 2015;290(5):2798-811.
18 Wauer T,Komander D.Structure of the human Parkin ligase domain in an autoinhibited state.EMBO J 2013;32(15):2099-112.
19 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 Commun2013;4:1982.
20 Okamoto K,Kondo-Okamoto N,Ohsumi Y.Mitochondriaanchored receptor Atg32 mediates degradation of mitochondria via selective autophagy.Dev Cell 2009;17(1):87-97.
21 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.
22 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.Autophagy2010;6(8):1090-106.
23 Lazarou M,Sliter DA,Kane LA,Sarraf SA,Wang C,Burman JL,et al.The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.Nature 2015;524(7565):309-14.
24 Chen M,Chen Z,Wang Y,Tan Z,Zhu C,Li Y,et al.Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy.Autophagy 2016;12(4):689-702.
25 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.
26 Park JS,Kang DH,Bae SH.p62 prevents carbonyl cyanide m-chlorophenyl hydrazine(CCCP)-induced apoptotic cell death by activating Nrf2.Biochem Biophys Res Commun 2015;464(4):1139-44.
27 Wang Y,Nartiss Y,Steipe B,Mc Quibban GA,Kim PK.ROSinduced mitochondrial depolarization initiates PARK2/PARKINdependent mitochondrial degradation by autophagy.Autophagy2012;8(10):1462-76.
28 Kanki T,Wang K,Cao Y,Baba M,Klionsky DJ.Atg32 is a mitochondrial protein that confers selectivity during mitophagy.Dev Cell 2009;17(1):98-109.
29 Wei X,Qi Y,Zhang X,Gu X,Cai H,Yang J,et al.ROS act as an upstream signal to mediate cadmium-induced mitophagy in mouse brain.Neurotoxicology 2015;46:19-24.
30 Wei X,Qi Y,Zhang X,Qiu Q,Gu X,Tao C,et al.Cadmium induces mitophagy through ROS-mediated PINK1/Parkin pathway.Toxicol Mech Methods 2014;24(7):504-11.
31 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.
32 Journo D,Mor A,Abeliovich H.Aup1-mediated regulation of Rtg3 during mitophagy.J Biol Chem 2009;284(51):35885-95.
33 Deffieu M,Bhatia-Kissova I,Salin B,Galinier A,Manon S,Camougrand N.Glutathione participates in the regulation of mitophagy in yeast.J Biol Chem 2009;284(22):14828-37.
34 Han R,Ji X,Rong R,Li Y,Yao W,Yuan J,et al.Mi R-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2.J Mol Med(Berl)2016;94(11):1267-79.
35 Maiuri MC,Le Toumelin G,Criollo A,Rain JC,Gautier F,Juin P,et al.Functional and physical interaction between Bcl-X(L)and a BH3-like domain in Beclin-1.EMBO J 2007;26(10):2527-39.
36 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.
37 Qu D,Hage A,Don-Carolis K,Huang E,Joselin A,Safarpour F,et al.BAG2 gene-mediated regulation of PINK1 protein is critical for mitochondrial translocation of PARKIN and neuronal survival.J Biol Chem 2015;290(51):30441-52.
38 Dai H,Deng Y,Zhang J,Han H,Zhao M,Li Y,et al.PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells.Toxicology 2015;334:72-80.
39 Johnson BN,Berger AK,Cortese GP,Lavoie MJ.The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax.Proc Natl Acad Sci USA 2012;109(16):6283-8.
40 Chen D,Gao F,Li B,Wang H,Xu Y,Zhu C,et al.Parkin monoubiquitinates Bcl-2 and regulates autophagy.J Biol Chem 2010;285(49):38214-23.
41 Garber K.Parkinson’s disease and cancer:the unexplored connection.J Natl Cancer Inst 2010;102(6):371-4.
42 Bartek J,Hodny Z.PARK2 orchestrates cyclins to avoid cancer.Nat Genet 2014;46(6):527-8.
43 Checler F,Alves da Costa C.Interplay between parkin and p53 governs a physiological homeostasis that is disrupted in Parkinson’s disease and cerebral cancer.Neurodegener Dis 2014;13 (2/3):118-21.
44 Tudzarova S,Mulholland P,Dey A,Stoeber K,Okorokov AL,Williams GH.p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress.Cell Cycle 2016;15(21):2958-72.
45 Zhang C,Lin M,Wu R,Wang X,Yang B,Levine AJ,et al.Parkin,a p53 target gene,mediates the role of p53 in glucose metabolism and the Warburg effect.Proc Natl Acad Sci USA2011;108(39):16259-64.
46 Requejo-Aguilar R,Lopez-Fabuel I,Fernandez E,Martins LM,Almeida A,Bolanos JP.PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1.Nat Commun 2014;5:4514.
47 Palacino JJ,Sagi D,Goldberg MS,Krauss S,Motz C,Wacker M,et al.Mitochondrial dysfunction and oxidative damage in parkindeficient mice.J Biol Chem 2004;279(18):18614-22.
48 Liu K,Li F,Han H,Chen Y,Mao Z,Luo J,et al.Parkin regulates the activity of pyruvate kinase M2.J Biol Chem 2016;291(19):10307-17.
49 Sabharwal SS,Schumacker PT.Mitochondrial ROS in cancer:Initiators,amplifiers or an Achilles’heel?Nat Rev Cancer 2014;14(11):709-21.
50 Abumrad NA,Moore DJ.Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36.J Clin Invest 2011;121(9):3389-92.
2 Dengjel J,Abeliovich H.Roles of mitophagy in cellular physiology and development.Cell Tissue Res 2017;367(1):95-109.
3 Lill CM.Genetics of Parkinson’s disease.Mol Cell Probes 2016;30(6):386-96.
4 Gispert S,Ricciardi F,Kurz A,Azizov M,Hoepken HH,Becker D,et al.Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.PLo S One 2009;4(6):e5777.
5 Matsui H,Gavinio R,Asano T,Uemura N,Ito H,Taniguchi Y,et al.PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates.Hum Mol Genet 2013;22(12):2423-34.
6 Triplett JC,Zhang Z,Sultana R,Cai J,Klein JB,Bueler H,et al.Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice:Insights into mechanisms of familial Parkinson’s disease.J Neurochem 2015;133(5):750-65.
7 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.
8 Morgante F,Fasano A,Ginevrino M,Petrucci S,Ricciardi L,Bove F,et al.Impulsive-compulsive behaviors in parkinassociated Parkinson disease.Neurology 2016;87(14):1436-41.
9 Bernardini JP,Lazarou M,Dewson G.Parkin and mitophagy in cancer.Oncogene 2017;36(10):1315-27.
10 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.
11 Callegari S,Oeljeklaus S,Warscheid B,Dennerlein S,Thumm M,Rehling P,et al.Phospho-ubiquitin-PARK2 complex as a marker for mitophagy defects.Autophagy 2017;13(1):201-11.
12 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.
13 Kane LA,Lazarou M,Fogel AI,Li Y,Yamano K,Sarraf SA,et al.PINK1 phosphorylates ubiquitin to activate Parkin E3ubiquitin ligase activity.J Cell Biol 2014;205(2):143-53.
14 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.
15 Wauer T,Simicek M,Schubert A,Komander D.Mechanism of phospho-ubiquitin-induced PARKIN activation.Nature 2015;524(7565):370-4.
16 Schulz C,Schendzielorz A,Rehling P.Unlocking the presequence import pathway.Trends Cell Biol 2015;25(5):265-75.
17 Aerts L,Craessaerts K,De Strooper B,Morais VA.PINK1 kinase catalytic activity is regulated by phosphorylation on serines 228and 402.J Biol Chem 2015;290(5):2798-811.
18 Wauer T,Komander D.Structure of the human Parkin ligase domain in an autoinhibited state.EMBO J 2013;32(15):2099-112.
19 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 Commun2013;4:1982.
20 Okamoto K,Kondo-Okamoto N,Ohsumi Y.Mitochondriaanchored receptor Atg32 mediates degradation of mitochondria via selective autophagy.Dev Cell 2009;17(1):87-97.
21 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.
22 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.Autophagy2010;6(8):1090-106.
23 Lazarou M,Sliter DA,Kane LA,Sarraf SA,Wang C,Burman JL,et al.The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.Nature 2015;524(7565):309-14.
24 Chen M,Chen Z,Wang Y,Tan Z,Zhu C,Li Y,et al.Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy.Autophagy 2016;12(4):689-702.
25 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.
26 Park JS,Kang DH,Bae SH.p62 prevents carbonyl cyanide m-chlorophenyl hydrazine(CCCP)-induced apoptotic cell death by activating Nrf2.Biochem Biophys Res Commun 2015;464(4):1139-44.
27 Wang Y,Nartiss Y,Steipe B,Mc Quibban GA,Kim PK.ROSinduced mitochondrial depolarization initiates PARK2/PARKINdependent mitochondrial degradation by autophagy.Autophagy2012;8(10):1462-76.
28 Kanki T,Wang K,Cao Y,Baba M,Klionsky DJ.Atg32 is a mitochondrial protein that confers selectivity during mitophagy.Dev Cell 2009;17(1):98-109.
29 Wei X,Qi Y,Zhang X,Gu X,Cai H,Yang J,et al.ROS act as an upstream signal to mediate cadmium-induced mitophagy in mouse brain.Neurotoxicology 2015;46:19-24.
30 Wei X,Qi Y,Zhang X,Qiu Q,Gu X,Tao C,et al.Cadmium induces mitophagy through ROS-mediated PINK1/Parkin pathway.Toxicol Mech Methods 2014;24(7):504-11.
31 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.
32 Journo D,Mor A,Abeliovich H.Aup1-mediated regulation of Rtg3 during mitophagy.J Biol Chem 2009;284(51):35885-95.
33 Deffieu M,Bhatia-Kissova I,Salin B,Galinier A,Manon S,Camougrand N.Glutathione participates in the regulation of mitophagy in yeast.J Biol Chem 2009;284(22):14828-37.
34 Han R,Ji X,Rong R,Li Y,Yao W,Yuan J,et al.Mi R-449a regulates autophagy to inhibit silica-induced pulmonary fibrosis through targeting Bcl2.J Mol Med(Berl)2016;94(11):1267-79.
35 Maiuri MC,Le Toumelin G,Criollo A,Rain JC,Gautier F,Juin P,et al.Functional and physical interaction between Bcl-X(L)and a BH3-like domain in Beclin-1.EMBO J 2007;26(10):2527-39.
36 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.
37 Qu D,Hage A,Don-Carolis K,Huang E,Joselin A,Safarpour F,et al.BAG2 gene-mediated regulation of PINK1 protein is critical for mitochondrial translocation of PARKIN and neuronal survival.J Biol Chem 2015;290(51):30441-52.
38 Dai H,Deng Y,Zhang J,Han H,Zhao M,Li Y,et al.PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells.Toxicology 2015;334:72-80.
39 Johnson BN,Berger AK,Cortese GP,Lavoie MJ.The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax.Proc Natl Acad Sci USA 2012;109(16):6283-8.
40 Chen D,Gao F,Li B,Wang H,Xu Y,Zhu C,et al.Parkin monoubiquitinates Bcl-2 and regulates autophagy.J Biol Chem 2010;285(49):38214-23.
41 Garber K.Parkinson’s disease and cancer:the unexplored connection.J Natl Cancer Inst 2010;102(6):371-4.
42 Bartek J,Hodny Z.PARK2 orchestrates cyclins to avoid cancer.Nat Genet 2014;46(6):527-8.
43 Checler F,Alves da Costa C.Interplay between parkin and p53 governs a physiological homeostasis that is disrupted in Parkinson’s disease and cerebral cancer.Neurodegener Dis 2014;13 (2/3):118-21.
44 Tudzarova S,Mulholland P,Dey A,Stoeber K,Okorokov AL,Williams GH.p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress.Cell Cycle 2016;15(21):2958-72.
45 Zhang C,Lin M,Wu R,Wang X,Yang B,Levine AJ,et al.Parkin,a p53 target gene,mediates the role of p53 in glucose metabolism and the Warburg effect.Proc Natl Acad Sci USA2011;108(39):16259-64.
46 Requejo-Aguilar R,Lopez-Fabuel I,Fernandez E,Martins LM,Almeida A,Bolanos JP.PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1.Nat Commun 2014;5:4514.
47 Palacino JJ,Sagi D,Goldberg MS,Krauss S,Motz C,Wacker M,et al.Mitochondrial dysfunction and oxidative damage in parkindeficient mice.J Biol Chem 2004;279(18):18614-22.
48 Liu K,Li F,Han H,Chen Y,Mao Z,Luo J,et al.Parkin regulates the activity of pyruvate kinase M2.J Biol Chem 2016;291(19):10307-17.
49 Sabharwal SS,Schumacker PT.Mitochondrial ROS in cancer:Initiators,amplifiers or an Achilles’heel?Nat Rev Cancer 2014;14(11):709-21.
50 Abumrad NA,Moore DJ.Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36.J Clin Invest 2011;121(9):3389-92.