title: Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.
abstract: Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway in vivo. However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome c within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome c is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Perier
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
authors.forename: Christelle
authors.initials: C
authors.lastname: Guégan
authors.forename: Casper
authors.initials: C
authors.lastname: Caspersen
authors.forename: Vernice
authors.initials: V
authors.lastname: Jackson-Lewis
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001205:Ascorbic Acid / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002308:Cardiolipins / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death; D002851:Chromatography, High Pressure Liquid; D045304:Cytochromes c / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D005821:Genetic Techniques; D006861:Hydrogen Peroxide / Q000737:chemistry; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism; D017382:Reactive Oxygen Species; D013347:Subcellular Fractions / Q000378:metabolism; D013367:Submitochondrial Particles / Q000473:pathology; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002308:Cardiolipins; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I; D001205:Ascorbic Acid; D010100:Oxygen