{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:31:14Z","timestamp":1790857874868,"version":"4.1.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,1,22]],"date-time":"2015-01-22T00:00:00Z","timestamp":1421884800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,1,22]],"date-time":"2015-01-22T00:00:00Z","timestamp":1421884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Huntington\u2019s disease (HD) is a fatal neurodegenerative disorder caused by aberrant expansion of CAG repeat in the\n                    <jats:italic>huntingtin<\/jats:italic>\n                    gene. Mutant Huntingtin (mHtt) alters multiple cellular processes, leading to neuronal dysfunction and death. Among those alterations, impaired mitochondrial metabolism seems to have a major role in HD pathogenesis. In this study, we used the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model system to further investigate the role of mitochondrial damages in HD. We first analyzed the impact of mHtt on mitochondrial morphology, and surprisingly, we revealed the formation of abnormal ring-shaped mitochondria in photoreceptor neurons. Because such mitochondrial spheroids were previously detected in cells where mitophagy is blocked, we analyzed the effect of PTEN-induced putative kinase 1 (PINK1), which controls Parkin-mediated mitophagy. Consistently, we found that PINK1 overexpression alleviated mitochondrial spheroid formation in HD flies. More importantly, PINK1 ameliorated ATP levels, neuronal integrity and adult fly survival, demonstrating that PINK1 counteracts the neurotoxicity of mHtt. This neuroprotection was Parkin-dependent and required mitochondrial outer membrane proteins, mitofusin and the voltage-dependent anion channel. Consistent with our observations in flies, we demonstrated that the removal of defective mitochondria was impaired in HD striatal cells derived from HdhQ111 knock-in mice, and that overexpressing PINK1 in these cells partially restored mitophagy. The presence of mHtt did not affect Parkin-mediated mitochondrial ubiquitination but decreased the targeting of mitochondria to autophagosomes. Altogether, our findings suggest that mitophagy is altered in the presence of mHtt and that increasing PINK1\/Parkin mitochondrial quality control pathway may improve mitochondrial integrity and neuroprotection in HD.\n                  <\/jats:p>","DOI":"10.1038\/cddis.2014.581","type":"journal-article","created":{"date-parts":[[2015,1,22]],"date-time":"2015-01-22T08:50:49Z","timestamp":1421916649000},"page":"e1617-e1617","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":221,"title":["PINK1-induced mitophagy promotes neuroprotection in Huntington\u2019s disease"],"prefix":"10.1038","volume":"6","author":[{"given":"B","family":"Khalil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"El Fissi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Aouane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M-J","family":"Cabirol-Pol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Rival","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J-C","family":"Li\u00e9vens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,1,22]]},"reference":[{"key":"BFcddis2014581_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/ana.410410514","volume":"41","author":"SE Browne","year":"1997","unstructured":"Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM et al. Oxidative damage and metabolic dysfunction in Huntington\u2019s disease: selective vulnerability of the basal ganglia. Ann Neurol 1997; 41: 646\u2013653.","journal-title":"Ann Neurol"},{"key":"BFcddis2014581_CR2","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1002\/ana.410390317","volume":"39","author":"M Gu","year":"1996","unstructured":"Gu M, Gash MT, Mann VM, Javoy-Agid F, Cooper JM, Schapira AH . Mitochondrial defect in Huntington\u2019s disease caudate nucleus. Ann Neurol 1996; 39: 385\u2013389.","journal-title":"Ann Neurol"},{"key":"BFcddis2014581_CR3","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.cell.2006.09.015","volume":"127","author":"L Cui","year":"2006","unstructured":"Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D . Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 2006; 127: 59\u201369.","journal-title":"Cell"},{"key":"BFcddis2014581_CR4","doi-asserted-by":"publisher","first-page":"3919","DOI":"10.1093\/hmg\/ddq306","volume":"19","author":"J Kim","year":"2010","unstructured":"Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K et al. Mitochondrial loss, dysfunction and altered dynamics in Huntington\u2019s disease. Hum Mol Genet 2010; 19: 3919\u20133935.","journal-title":"Hum Mol Genet"},{"key":"BFcddis2014581_CR5","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1093\/hmg\/ddr475","volume":"21","author":"UP Shirendeb","year":"2012","unstructured":"Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL et al. Mutant huntingtin\u2019s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington\u2019s disease. Hum Mol Genet 2012; 21: 406\u2013420.","journal-title":"Hum Mol Genet"},{"key":"BFcddis2014581_CR6","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/nm.2313","volume":"17","author":"W Song","year":"2011","unstructured":"Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 2011; 17: 377\u2013382.","journal-title":"Nat Med"},{"key":"BFcddis2014581_CR7","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1083\/jcb.200910140","volume":"189","author":"N Matsuda","year":"2010","unstructured":"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: 211\u2013221.","journal-title":"J Cell Biol"},{"key":"BFcddis2014581_CR8","doi-asserted-by":"publisher","first-page":"e1000298","DOI":"10.1371\/journal.pbio.1000298","volume":"8","author":"DP Narendra","year":"2010","unstructured":"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: e1000298.","journal-title":"PLoS Biol"},{"key":"BFcddis2014581_CR9","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1073\/pnas.0911187107","volume":"107","author":"C Vives-Bauza","year":"2010","unstructured":"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 Natl Acad Sci USA 2010; 107: 378\u2013383.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014581_CR10","doi-asserted-by":"publisher","first-page":"42379","DOI":"10.1074\/jbc.M112.413682","volume":"287","author":"WX Ding","year":"2012","unstructured":"Ding WX, Guo F, Ni HM, Bockus A, Manley S, Stolz DB et al. Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J Biol Chem 2012; 287: 42379\u201342388.","journal-title":"J Biol Chem"},{"key":"BFcddis2014581_CR11","doi-asserted-by":"publisher","first-page":"42373","DOI":"10.1074\/jbc.M112.413674","volume":"287","author":"WX Ding","year":"2012","unstructured":"Ding WX, Li M, Biazik JM, Morgan DG, Guo F, Ni HM et al. Electron microscopic analysis of a spherical mitochondrial structure. J Biol Chem 2012; 287: 42373\u201342378.","journal-title":"J Biol Chem"},{"key":"BFcddis2014581_CR12","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1093\/hmg\/ddm360","volume":"17","author":"JC Li\u00e9vens","year":"2008","unstructured":"Li\u00e9vens JC, Iche M, Laval M, Faivre-Sarrailh C, Birman S . AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington\u2019s disease. Hum Mol Genet 2008; 17: 882\u2013894.","journal-title":"Hum Mol Genet"},{"key":"BFcddis2014581_CR13","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1038\/nature04788","volume":"441","author":"J Park","year":"2006","unstructured":"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: 1157\u20131161.","journal-title":"Nature"},{"key":"BFcddis2014581_CR14","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.bbrc.2008.11.086","volume":"378","author":"J Park","year":"2009","unstructured":"Park J, Lee G, Chung J . The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem Biophys Res Commun 2009; 378: 518\u2013523.","journal-title":"Biochem Biophys Res Commun"},{"key":"BFcddis2014581_CR15","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1089\/ars.2010.3799","volume":"14","author":"DP Narendra","year":"2011","unstructured":"Narendra DP, Youle RJ . Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid Redox Signal 2011; 14: 1929\u20131938.","journal-title":"Antioxid Redox Signal"},{"key":"BFcddis2014581_CR16","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/ncb2012","volume":"12","author":"S Geisler","year":"2010","unstructured":"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: 119\u2013131.","journal-title":"Nat Cell Biol"},{"key":"BFcddis2014581_CR17","doi-asserted-by":"publisher","first-page":"40652","DOI":"10.1074\/jbc.M112.419721","volume":"287","author":"Y Sun","year":"2012","unstructured":"Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L . Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. J Biol Chem 2012; 287: 40652\u201340660.","journal-title":"J Biol Chem"},{"key":"BFcddis2014581_CR18","doi-asserted-by":"publisher","first-page":"e172","DOI":"10.1371\/journal.pbio.0050172","volume":"5","author":"JW Pridgeon","year":"2007","unstructured":"Pridgeon JW, Olzmann JA, Chin LS, Li L . PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 2007; 5: e172.","journal-title":"PLoS Biol"},{"key":"BFcddis2014581_CR19","doi-asserted-by":"publisher","first-page":"e467","DOI":"10.1038\/cddis.2012.205","volume":"4","author":"AC Costa","year":"2013","unstructured":"Costa AC, Loh SH, Martins LM . Drosophila Trap1 protects against mitochondrial dysfunction in a PINK1\/parkin model of Parkinson\u2019s disease. Cell Death Dis 2013; 4: e467.","journal-title":"Cell Death Dis"},{"key":"BFcddis2014581_CR20","doi-asserted-by":"publisher","first-page":"2799","DOI":"10.1093\/hmg\/9.19.2799","volume":"9","author":"F Trettel","year":"2000","unstructured":"Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F et al. Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Mol Genet 2000; 9: 2799\u20132809.","journal-title":"Hum Mol Genet"},{"key":"BFcddis2014581_CR21","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.4161\/auto.6.8.13426","volume":"6","author":"D Narendra","year":"2010","unstructured":"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: 1090\u20131106.","journal-title":"Autophagy"},{"key":"BFcddis2014581_CR22","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1093\/hmg\/ddn404","volume":"18","author":"H Wang","year":"2009","unstructured":"Wang H, Lim PJ, Karbowski M, Monteiro MJ . Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet 2009; 18: 737\u2013752.","journal-title":"Hum Mol Genet"},{"key":"BFcddis2014581_CR23","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1002\/emmm.201000102","volume":"2","author":"V Costa","year":"2010","unstructured":"Costa V, Giacomello M, Hudec R, Lopreiato R, Ermak G, Lim D et al. Mitochondrial fission and cristae disruption increase the response of cell models of Huntington\u2019s disease to apoptotic stimuli. EMBO Mol Med 2010; 2: 490\u2013503.","journal-title":"EMBO Mol Med"},{"key":"BFcddis2014581_CR24","doi-asserted-by":"publisher","first-page":"5371","DOI":"10.1172\/JCI70911","volume":"123","author":"X Guo","year":"2013","unstructured":"Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D, Qi X . Inhibition of mitochondrial fragmentation diminishes Huntington\u2019s disease-associated neurodegeneration. J Clin Invest 2013; 123: 5371\u20135388.","journal-title":"J Clin Invest"},{"key":"BFcddis2014581_CR25","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.4161\/auto.24871","volume":"9","author":"XM Yin","year":"2013","unstructured":"Yin XM, Ding WX . The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation. Autophagy 2013; 9: 1687\u20131692.","journal-title":"Autophagy"},{"key":"BFcddis2014581_CR26","doi-asserted-by":"publisher","first-page":"14474","DOI":"10.1074\/jbc.M600364200","volume":"281","author":"M Shibata","year":"2006","unstructured":"Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem 2006; 281: 14474\u201314485.","journal-title":"J Biol Chem"},{"key":"BFcddis2014581_CR27","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/nn.2528","volume":"13","author":"M Martinez-Vicente","year":"2010","unstructured":"Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington\u2019s disease. Nat Neurosci 2010; 13: 567\u2013576.","journal-title":"Nat Neurosci"},{"key":"BFcddis2014581_CR28","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1523\/JNEUROSCI.1870-13.2014","volume":"34","author":"YC Wong","year":"2014","unstructured":"Wong YC, Holzbaur EL . The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci 2014; 34: 1293\u20131305.","journal-title":"J Neurosci"},{"key":"BFcddis2014581_CR29","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1073\/pnas.0705363105","volume":"105","author":"ME Haque","year":"2008","unstructured":"Haque ME, Thomas KJ, D\u2019Souza C, Callaghan S, Kitada T, Slack RS et al. Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci USA 2008; 105: 1716\u20131721.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2014581_CR30","doi-asserted-by":"publisher","first-page":"34025","DOI":"10.1074\/jbc.M505143200","volume":"280","author":"A Petit","year":"2005","unstructured":"Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid M et al. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 2005; 280: 34025\u201334032.","journal-title":"J Biol Chem"},{"key":"BFcddis2014581_CR31","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1139\/G08-085","volume":"51","author":"AM Todd","year":"2008","unstructured":"Todd AM, Staveley BE . Pink1 suppresses alpha-synuclein-induced phenotypes in a Drosophila model of Parkinson\u2019s disease. Genome 2008; 51: 1040\u20131046.","journal-title":"Genome"},{"key":"BFcddis2014581_CR32","doi-asserted-by":"publisher","first-page":"22019","DOI":"10.1074\/jbc.M113.467530","volume":"288","author":"M Iguchi","year":"2013","unstructured":"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: 22019\u201322032.","journal-title":"J Biol Chem"},{"key":"BFcddis2014581_CR33","doi-asserted-by":"publisher","first-page":"120080","DOI":"10.1098\/rsob.120080","volume":"2","author":"C Kondapalli","year":"2012","unstructured":"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: 120080.","journal-title":"Open Biol"},{"key":"BFcddis2014581_CR34","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/srep01002","volume":"2","author":"K Shiba-Fukushima","year":"2012","unstructured":"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.","journal-title":"Sci Rep"},{"key":"BFcddis2014581_CR35","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1083\/jcb.201007013","volume":"191","author":"A Tanaka","year":"2010","unstructured":"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: 1367\u20131380.","journal-title":"J Cell Biol"},{"key":"BFcddis2014581_CR36","doi-asserted-by":"publisher","first-page":"1726","DOI":"10.1093\/hmg\/ddr048","volume":"20","author":"NC Chan","year":"2011","unstructured":"Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 2011; 20: 1726\u20131737.","journal-title":"Hum Mol Genet"},{"key":"BFcddis2014581_CR37","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1126\/science.1231031","volume":"340","author":"Y Chen","year":"2013","unstructured":"Chen Y, Dorn GW II . PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 2013; 340: 471\u2013475.","journal-title":"Science"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2014581.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2014581","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2014581.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:08:19Z","timestamp":1672895299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2014581"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,22]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,1]]}},"alternative-id":["BFcddis2014581"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2014.581","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,22]]},"assertion":[{"value":"9 July 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2014","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2014","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}