title: ATP13A2 regulates mitochondrial bioenergetics through macroautophagy.
abstract: Mitochondrial dysfunction and autophagy are centrally implicated in Parkinson's disease (PD). Mutations in ATP13A2, which encodes a lysosomal P-type ATPase of unknown function, cause a rare, autosomal recessive parkinsonian syndrome. Lysosomes are essential for autophagy, and autophagic clearance of dysfunctional mitochondria represents an important element of mitochondrial quality control. In this study, we tested the hypothesis that loss of ATP13A2 function will affect mitochondrial function. Knockdown of ATP13A2 led to an increase in mitochondrial mass in primary mouse cortical neurons and in SH-SY5Y cells forced into mitochondrial dependence. ATP13A2-deficient cells exhibited increased oxygen consumption without a significant change in steady-state levels of ATP. Mitochondria in knockdown cells exhibited increased fragmentation and increased production of reactive oxygen species (ROS). Basal levels of the autophagosome marker LC3-II were not significantly changed, however, ATP13A2 knockdown cells exhibited decreased autophagic flux, associated with increased levels of phospho-mTOR, and resistance to autophagy induction by rapamycin. The effects of ATP13A2 siRNA on oxygen consumption, mitochondrial mass and ROS production could be mimicked by inhibiting autophagy induction using siRNA to Atg7. We propose that decreased autophagy associated with ATP13A2 deficiency affects mitochondrial quality control, resulting in increased ROS production. These data are the first to implicate loss of ATP13A2 function in mitochondrial maintenance and oxidative stress, lending further support to converging genetic and environmental evidence for mitochondrial dysregulation in PD pathogenesis.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Gusdon
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhu
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018274:Electroporation; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C502661:Atg7 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018942:Macrolides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C057620:bafilomycin A; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; C088641:ATP12A protein, human; D017506:H(+)-K(+)-Exchanging ATPase; D000071193:Autophagy-Related Protein 7