线粒体自噬的调控机制及其在相关疾病中的作用
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摘要
线粒体自噬(mitophagy)是指特异清除受损或多余线粒体的过程,是一种重要的线粒体质量控制机制。线粒体自噬功能障碍或线粒体自噬过度激活都会破坏线粒体稳态,影响机体健康甚至导致死亡。主要讨论了在酵母和哺乳动物细胞中发现的正向调控线粒体自噬的机制:在酵母中,线粒体自噬是由自噬相关蛋白32(autophagy-related protein 32,Atg32)介导的;而哺乳动物体内线粒体自噬的调控途径主要有3种:PTEN诱导激酶1(PTEN-induced kinase 1,PINK1)/E3泛素连接酶Parkin途径、类NIP3蛋白X(NIP3-like protein X,Nix)途径、携带FUN14结构域蛋白1(FUN14 domain-containing protein 1,UNDC1)途径,此外,还有几种新发现的线粒体自噬受体也能够介导线粒体的特异清除。并对目前研究较少的线粒体自噬的负调控机制进行了综述。最后探讨了线粒体自噬功能异常与人类疾病(如帕金森症)的关联。通过深入剖析线粒体自噬发生的分子机制,以期为进一步研究与线粒体自噬功能异常相关的疾病的治疗提供理论基础。
Mitophagy refers to the process of specifically removing damaged or redundant mitochondria, and it is an important mitochondrial quality control mechanism. Dysfunction or excessive activation of mitophagy will destroy mitochondrial homeostasis, affect body health and even lead to death. The mechanisms of positive regulation of mitophagy found in yeast and mammalian cells were mainly discussed. In yeast, mitophagy was mediated by autophagy-related protein 32(Atg32), while there were mainly three regulatory pathways of mitophagy in mammals: PTEN-induced kinase 1(PTEN-induced kinase 1, PINK1)/E3 ubiquitin ligase Parkin pathway, NIP3-like protein X(NIP3-like protein X, Nix) pathway and FUN14 domain-containing protein 1(UNDC1) pathway. In addition, several newly discovered mitophagy receptors could also mediate mitochondrial specific clearance. Moreover, the mechanisms of negative regulation of mitophagy, which were seldom studied at present, were reviewed. Finally, the relationship between abnormal mitophagy and human diseases(such as Parkinson's disease) was discussed. The molecular mechanism of the occurrence of mitophagy was in-depth analyzed in order to provide theoretical basis for further research on the treatment of diseases related to abnormal mitophagy.
Mitophagy refers to the process of specifically removing damaged or redundant mitochondria, and it is an important mitochondrial quality control mechanism. Dysfunction or excessive activation of mitophagy will destroy mitochondrial homeostasis, affect body health and even lead to death. The mechanisms of positive regulation of mitophagy found in yeast and mammalian cells were mainly discussed. In yeast, mitophagy was mediated by autophagy-related protein 32(Atg32), while there were mainly three regulatory pathways of mitophagy in mammals: PTEN-induced kinase 1(PTEN-induced kinase 1, PINK1)/E3 ubiquitin ligase Parkin pathway, NIP3-like protein X(NIP3-like protein X, Nix) pathway and FUN14 domain-containing protein 1(UNDC1) pathway. In addition, several newly discovered mitophagy receptors could also mediate mitochondrial specific clearance. Moreover, the mechanisms of negative regulation of mitophagy, which were seldom studied at present, were reviewed. Finally, the relationship between abnormal mitophagy and human diseases(such as Parkinson's disease) was discussed. The molecular mechanism of the occurrence of mitophagy was in-depth analyzed in order to provide theoretical basis for further research on the treatment of diseases related to abnormal mitophagy.
引文
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[37] Cunningham C N,Baughman J M,Phu L,et al..USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria[J].Nat.Cell Biol.,2015,17(2):160-169.
[38] Durcan T M,Tang M Y,Pérusse J R,et al..USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin[J].EMBO J.,2014,33(21):2473-2491.
[39] Wauer T,Swatek K N,Wagstaff J L,et al..Ubiquitin Ser65 phosphorylation affects ubiquitin structure,chain assembly and hydrolysis[J].EMBO J.,2015,34(3):307-325.
[40] Wang L,Cho Y L,Tang Y,et al..PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-Parkin-mediated mitophagy[J].Cell Res.,2018,28(8):787-802.
[41] Heo J M,Ordureau A,Paulo J A,et al..The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy[J].Mol.Cell,2015,60(1):7-20.
[42] Lazarou M,Sliter D A,Kane L A,et al..The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy[J].Nature,2015,524(7565):309-314.
[43] Valente E M,Abou-Sleiman P M,Caputo V,et al..Hereditary early-onset Parkinson’s disease caused by mutations in PINK1[J].Science,2004,304(5674):1158-1160.
[44] Kitada T,Asakawa S,Hattori N,et al..Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism[J].Nature,1998,392(6676):605-608.
[45] Narendra D P,Jin S M,Tanaka A,et al..PINK1 is selectively stabilized on impaired mitochondria to activate Parkin[J].PLoS Biol.,2010,8(1):e1000298.
[46] Narendra D,Tanaka A,Suen D F,et al..Parkin is recruited selectively to impaired mitochondria and promotes their autophagy[J].J.Cell Biol.,2008,183(5):795-803.
[47] Sliter D A,Martinez J,Hao L,et al..Parkin and PINK1 mitigate STING-induced inflammation[J].Nature,2018,561(7722):258-262.
[48] Ramirez A,Heimbach A,Gründemann J,et al..Hereditary parkinsonism with dementia is caused by mutations in ATP13A2,encoding a lysosomal type 5 P-type ATPase[J].Nat.Genet.,2006,38(10):1184-1191.
[49] Grünewald A,Arns B,Seibler P,et al..ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome[J].Neurobiol.Aging,2012,33(8):1843.e1-1843.e7.
[50] Burchell V S,Nelson D E,Sanchez-Martinez A,et al..The Parkinson’s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy[J].Nat.Neurosci.,2013,16(9):1257-1265.
[51] Kerr J S,Adriaanse B A,Greig N H,et al..Mitophagy and Alzheimer’s disease:Cellular and molecular mechanisms[J].Trends Neurosci.,2017,40(3):151-166.
[52] Du F,Yu Q,Yan S,et al..PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease[J].Brain,2017,140(12):3233-3251.
[53] Martín-Maestro P,Gargini R,Perry G,et al..PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer’s disease[J].Hum.Mol.Genet.,2015,25(4):792-806.
[54] Dagda R K,Cherra S J,Kulich S M,et al..Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission[J].J.Biol.Chem.,2009,284(20):13843-13855.
[55] Chakrabarti L,Eng J,Ivanov N,et al..Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death[J].Mol.Brain,2009,2(1):24.
[56] Shi R Y,Zhu S H,Li V,et al..BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke[J].CNS Neurosci.Ther.,2014,20(12):1045-1055.
[57] Lee Y,Kwon I,Jang Y,et al..Potential signaling pathways of acute endurance exercise-induced cardiac autophagy and mitophagy and its possible role in cardioprotection[J].J.Physiol.Sci.,2017,67(6):639-654.
[58] Scheibye-Knudsen M,Fang E F,Croteau D L,et al..Protecting the mitochondrial powerhouse[J].Trends Cell Biol.,2015,25(3):158-170.
[2] Rubinsztein D C,Codogno P,Levine B.Autophagy modulation as a potential therapeutic target for diverse diseases[J].Nat.Rev.Drug Discov.,2012,11(9):709-730.
[3] Kim I,Rodriguez-Enriquez S,Lemasters J J.Selective degradation of mitochondria by mitophagy[J].Arch.Biochem.Biophys.,2007,462(2):245-253.
[4] Nakatogawa H,Ichimura Y,Ohsumi Y.Atg8,a ubiquitin-like protein required for autophagosome formation,mediates membrane tethering and hemifusion[J].Cell,2007,130(1):165-178.
[5] Lisanti M P,Martinez-Outschoorn U E,Chiavarina B,et al..Understanding the “lethal” drivers of tumor-stroma co-evolution:Emerging role(s) for hypoxia,oxidative stress and autophagy/mitophagy in the tumor microenvironment[J].Cancer Biol.Ther.,2010,10(6):537-542.
[6] Priault M,Salin B,Schaeffer J,et al..Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast[J].Cell Death Differ.,2005,12(12):1613-1621.
[7] He C,Song H,Yorimitsu T,et al..Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast[J].J.Cell Biol.,2006,175(6):925-935.
[8] Kanki T,Wang K,Cao Y,et al..Atg32 is a mitochondrial protein that confers selectivity during mitophagy[J].Dev.Cell,2009,17(1):98-109.
[9] Aoki Y,Kanki T,Hirota Y,et al..Phosphorylation of Serine 114 on Atg32 mediates mitophagy[J].Mol.Biol.Cell,2011,22(17):3206-3217.
[10] Noda N N,Ohsumi Y,Inagaki F.Atg8-family interacting motif crucial for selective autophagy[J].FEBS Lett.,2010,584(7):1379-1385.
[11] Sakakibara K,Eiyama A,Suzuki S W,et al..Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling[J].EMBO J.,2015,34(21):2703-2719.
[12] Okamoto K,Kondo-Okamoto N,Ohsumi Y.Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy[J].Dev.Cell,2009,17(1):87-97.
[13] Whitworth A J,Pallanck L J.The PINK1/Parkin pathway:A mitochondrial quality control system?[J].J.Bioenerg.Biomembr.,2009,41(6):499-503.
[14] Lazarou M,Jin S M,Kane L A,et al..Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin[J].Dev.Cell,2012,22(2):320-333.
[15] Schubert A F,Gladkova C,Pardon E,et al..Structure of PINK1 in complex with its substrate ubiquitin[J].Nature,2017,552(7683):51-56.
[16] Okatsu K,Oka T,Iguchi M,et al..PINK1 autophosphoryla-tion upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria[J].Nat.Commun.,2012,3:1016.
[17] Geisler S,Holmstr?m K M,Skujat D,et al..PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1[J].Nat.Cell Biol.,2010,12(2):119-131.
[18] Matsuda N,Sato S,Shiba K,et al..PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy[J].J.Cell Biol.,2010,189(2):211-221.
[19] Koyano F,Okatsu K,Kosako H,et al..Ubiquitin is phosphorylated by PINK1 to activate parkin[J].Nature,2014,510(7503):162-166.
[20] Green D R,Levine B.To be or not to be?How selective autophagy and cell death govern cell fate[J].Cell,2014,157(1):65-75.
[21] Twig G,Elorza A,Molina A J A,et al..Fission and selective fusion govern mitochondrial segregation and elimination by autophagy[J].EMBO J.,2008,27(2):433-446.
[22] Poole A C,Thomas R E,Andrews L A,et al..The PINK1/Parkin pathway regulates mitochondrial morphology[J].Proc.Natl.Acad.Sci.USA,2008,105(5):1638-1643.
[23] Poole A C,Thomas R E,Yu S,et al..The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway[J].PLoS ONE,2010,5(4):e10054.
[24] Wang X,Winter D,Ashrafi G,et al..PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility[J].Cell,2011,147(4):893-906.
[25] Sandoval H,Thiagarajan P,Dasgupta S K,et al..Essential role for Nix in autophagic maturation of erythroid cells[J].Nature,2008,454(7201):232-235.
[26] Novak I,Kirkin V,McEwan D G,et al..Nix is a selective autophagy receptor for mitochondrial clearance[J].EMBO Rep.,2010,11(1):45-51.
[27] Xiang G,Yang L,Long Q,et al..BNIP3L-dependent mitophagy accounts for mitochondrial clearance during 3 factors-induced somatic cell reprogramming[J].Autophagy,2017,13(9):1543-1555.
[28] Liu L,Feng D,Chen G,et al..Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells[J].Nat.Cell Biol.,2012,14(2):177-185.
[29] Lv M,Wang C,Li F,et al..Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy[J].Protein Cell,2017,8(1):25-38.
[30] Chen Z,Liu L,Cheng Q,et al..Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy[J].EMBO Rep.,2017,18(3):495-509.
[31] Chen M,Chen Z,Wang Y,et al..Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy[J].Autophagy,2016,12(4):689-702.
[32] Otsu K,Murakawa T,Yamaguchi O.BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32[J].Autophagy,2015,11(10):1932-1933.
[33] Zhang Y,Yao Y,Qiu X,et al..Listeria hijacks host mitophagy through a novel mitophagy receptor to evade killing[J].Nat.Immunol.,2019,20(4):433-446.
[34] Wei Y,Chiang W C,Sumpter J R,et al..Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor[J].Cell,2017,168(1-2):224-238.
[35] Cornelissen T,Haddad D,Wauters F,et al..The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy[J].Hum.Mol.Genet.,2014,23(19):5227-5242.
[36] Bingol B,Tea J S,Phu L,et al..The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy[J].Nature,2014,510(7505):370-375.
[37] Cunningham C N,Baughman J M,Phu L,et al..USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria[J].Nat.Cell Biol.,2015,17(2):160-169.
[38] Durcan T M,Tang M Y,Pérusse J R,et al..USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin[J].EMBO J.,2014,33(21):2473-2491.
[39] Wauer T,Swatek K N,Wagstaff J L,et al..Ubiquitin Ser65 phosphorylation affects ubiquitin structure,chain assembly and hydrolysis[J].EMBO J.,2015,34(3):307-325.
[40] Wang L,Cho Y L,Tang Y,et al..PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-Parkin-mediated mitophagy[J].Cell Res.,2018,28(8):787-802.
[41] Heo J M,Ordureau A,Paulo J A,et al..The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy[J].Mol.Cell,2015,60(1):7-20.
[42] Lazarou M,Sliter D A,Kane L A,et al..The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy[J].Nature,2015,524(7565):309-314.
[43] Valente E M,Abou-Sleiman P M,Caputo V,et al..Hereditary early-onset Parkinson’s disease caused by mutations in PINK1[J].Science,2004,304(5674):1158-1160.
[44] Kitada T,Asakawa S,Hattori N,et al..Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism[J].Nature,1998,392(6676):605-608.
[45] Narendra D P,Jin S M,Tanaka A,et al..PINK1 is selectively stabilized on impaired mitochondria to activate Parkin[J].PLoS Biol.,2010,8(1):e1000298.
[46] Narendra D,Tanaka A,Suen D F,et al..Parkin is recruited selectively to impaired mitochondria and promotes their autophagy[J].J.Cell Biol.,2008,183(5):795-803.
[47] Sliter D A,Martinez J,Hao L,et al..Parkin and PINK1 mitigate STING-induced inflammation[J].Nature,2018,561(7722):258-262.
[48] Ramirez A,Heimbach A,Gründemann J,et al..Hereditary parkinsonism with dementia is caused by mutations in ATP13A2,encoding a lysosomal type 5 P-type ATPase[J].Nat.Genet.,2006,38(10):1184-1191.
[49] Grünewald A,Arns B,Seibler P,et al..ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome[J].Neurobiol.Aging,2012,33(8):1843.e1-1843.e7.
[50] Burchell V S,Nelson D E,Sanchez-Martinez A,et al..The Parkinson’s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy[J].Nat.Neurosci.,2013,16(9):1257-1265.
[51] Kerr J S,Adriaanse B A,Greig N H,et al..Mitophagy and Alzheimer’s disease:Cellular and molecular mechanisms[J].Trends Neurosci.,2017,40(3):151-166.
[52] Du F,Yu Q,Yan S,et al..PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease[J].Brain,2017,140(12):3233-3251.
[53] Martín-Maestro P,Gargini R,Perry G,et al..PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer’s disease[J].Hum.Mol.Genet.,2015,25(4):792-806.
[54] Dagda R K,Cherra S J,Kulich S M,et al..Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission[J].J.Biol.Chem.,2009,284(20):13843-13855.
[55] Chakrabarti L,Eng J,Ivanov N,et al..Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death[J].Mol.Brain,2009,2(1):24.
[56] Shi R Y,Zhu S H,Li V,et al..BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke[J].CNS Neurosci.Ther.,2014,20(12):1045-1055.
[57] Lee Y,Kwon I,Jang Y,et al..Potential signaling pathways of acute endurance exercise-induced cardiac autophagy and mitophagy and its possible role in cardioprotection[J].J.Physiol.Sci.,2017,67(6):639-654.
[58] Scheibye-Knudsen M,Fang E F,Croteau D L,et al..Protecting the mitochondrial powerhouse[J].Trends Cell Biol.,2015,25(3):158-170.