title: Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival.
abstract: Sustained cellular function and viability of high-energy demanding post-mitotic cells rely on the continuous supply of ATP. The utilization of mitochondrial oxidative phosphorylation for efficient ATP generation is a function of oxygen levels. As such, oxygen deprivation, in physiological or pathological settings, has profound effects on cell metabolism and survival. Here we show that mild extracellular acidosis, a physiological consequence of anaerobic metabolism, can reprogramme the mitochondrial metabolic pathway to preserve efficient ATP production regardless of oxygen levels. Acidosis initiates a rapid and reversible homeostatic programme that restructures mitochondria, by regulating mitochondrial dynamics and cristae architecture, to reconfigure mitochondrial efficiency, maintain mitochondrial function and cell survival. Preventing mitochondrial remodelling results in mitochondrial dysfunction, fragmentation and cell death. Our findings challenge the notion that oxygen availability is a key limiting factor in oxidative metabolism and brings forth the concept that mitochondrial morphology can dictate the bioenergetic status of post-mitotic cells.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Khacho
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tarabay
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada [2].
authors.forename: David
authors.initials: D
authors.lastname: Patten
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada [2].
authors.forename: Pamela
authors.initials: P
authors.lastname: Khacho
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Jason G
authors.initials: JG
authors.lastname: MacLaurin
authors.affiliation: Department of Physiology and Pharmacology, J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Guadagno
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada [2] Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Bergeron
authors.affiliation: Department of Physiology and Pharmacology, J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cregan
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
mesh_terms: D000138:Acidosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008938:Mitosis; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate; D010100:Oxygen