Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival

• Published in: Nature communications 2014-04, Vol.5 (1), p.3550-3550, Article 3550
• Main Authors: Khacho, Mireille, Tarabay, Michelle, Patten, David, Khacho, Pamela, MacLaurin, Jason G., Guadagno, Jennifer, Bergeron, Richard, Cregan, Sean P., Harper, Mary-Ellen, Park, David S., Slack, Ruth S.
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/51; 13/89; 14/1; 14/19; 14/28; 631/443/319; 631/80/642/333; Acidosis - genetics; Acidosis - metabolism; Acidosis - physiopathology; Adenosine Triphosphate - metabolism; Animals; Cell Line, Tumor; Cell Survival; Female; Humanities and Social Sciences; Humans; Male; Metabolic Networks and Pathways; Mice; Mitochondria - metabolism; Mitosis; multidisciplinary; Oxidative Phosphorylation; Oxygen - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4550

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. In hypoxic conditions, cells depend on anaerobic respiration, which results in extracellular acidosis. Khacho et al. find that acidosis serves a protective function, enhancing mitochondrial respiratory capacity and sustaining ATP synthesis despite limited oxygen availability, by both promoting mitochondrial fusion and inhibiting fission.