title: PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity.
abstract: Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an age-dependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.
authors.affiliation: Department of Pharmacology, Mitochondria Hub Regulation Center (MHRC), Dong-A University College of Medicine, Busan 602-714, Korea. hjkoh@dau.ac.kr
authors.forename: Hyongjong
authors.initials: H
authors.lastname: Koh
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D051858:Forkhead Transcription Factors; D006655:Histone Deacetylases; D017346:Protein Serine-Threonine Kinases; D037761:Sirtuins; D044767:Ubiquitin-Protein Ligases; C477334:FOXO protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C447899:Sirt2 protein, Drosophila; C487430:park protein, Drosophila