title: Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death.
abstract: Acid-sensing ion channel 1a (ASIC1a) is the key proton receptor in nervous systems, mediating acidosis-induced neuronal injury in many neurological disorders, such as ischemic stroke. Up to now, functional ASIC1a has been found exclusively on the plasma membrane. Here, we show that ASIC1a proteins are also present in mitochondria of mouse cortical neurons where they are physically associated with adenine nucleotide translocase. Moreover, purified mitochondria from ASIC1a(-/-) mice exhibit significantly enhanced Ca(2+) retention capacity and accelerated Ca(2+) uptake rate. When challenged with hydrogen peroxide (H2O2), ASIC1a(-/-) neurons are resistant to cytochrome c release and inner mitochondrial membrane depolarization, suggesting an impairment of mitochondrial permeability transition (MPT) due to ASIC1a deletion. Consistently, H2O2-induced neuronal death, which is MPT dependent, is reduced in ASIC1a(-/-) neurons. Additionally, significant increases in mitochondrial size and oxidative stress levels are detected in ASIC1a(-/-) mouse brain, which also displays marked changes (>2-fold) in the expression of mitochondrial proteins closely related to reactive oxygen species signal pathways, as revealed by two-dimensional difference gel electrophoresis followed by mass spectrometry analysis. Our data suggest that mitochondrial ASIC1a may serve as an important regulator of MPT pores, which contributes to oxidative neuronal cell death.
authors.affiliation: Departments of Anatomy and Embryology, Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Wang
authors.forename: W-Z
authors.initials: WZ
authors.lastname: Zeng
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: X-L
authors.initials: XL
authors.lastname: Song
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: D
authors.initials: D
authors.lastname: Tang
authors.forename: X-P
authors.initials: XP
authors.lastname: Dong
authors.forename: M X
authors.initials: MX
authors.lastname: Zhu
authors.forename: T-L
authors.initials: TL
authors.lastname: Xu
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D017382:Reactive Oxygen Species