title: PINK1-induced mitophagy promotes neuroprotection in Huntington's disease.
abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by aberrant expansion of CAG repeat in the huntingtin 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 Drosophila 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.
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286, 13344 Marseille, France.
authors.forename: B
authors.initials: B
authors.lastname: Khalil
authors.affiliation: Aix-Marseille Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, 13288 Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: El Fissi
authors.affiliation: Aix-Marseille Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, 13288 Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Aouane
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286, 13344 Marseille, France.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Cabirol-Pol
authors.affiliation: Aix-Marseille Université, CNRS, Institut de Biologie du Développement de Marseille, UMR 7288, 13288 Marseille, France.
authors.forename: T
authors.initials: T
authors.lastname: Rival
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, UMR 7286, 13344 Marseille, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Liévens
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D063306:Mitophagy; D050505:Mutant Proteins / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D011494:Protein Kinases / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D050505:Mutant Proteins; D018696:Neuroprotective Agents; D011494:Protein Kinases; D050486:Serotonin Plasma Membrane Transport Proteins; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C493231:Slc6a4 protein, mouse; C111567:parkin protein