Mitochondrial fragmentation leads to intracellular acidification in Caenorhabditis elegans and mammalian cells.
Mitochondrial structural dynamics are regulated through the opposing processes of membrane fission and fusion, which are conserved from yeast to man. The chronic inhibition of mitochondrial fusion as a result of genetic mutation is the cause of human autosomal dominant optic atrophy (ADOA) and Charcot-Marie-Tooth syndrome type 2A (CMT-2A). Here, we demonstrate that genetic fragmentation of the mitochondrial network in Caenorhabditis elegans induces cellular acidification in a broad range of tissues from the intestine, to body wall muscles, and neurons. Genetic epistasis analyses demonstrate that fragmentation itself, and not the loss of a particular protein, leads to acidosis, and the worm's fitness matches the extent of acidification. We suggest that fragmentation may cause acidification through two distinct processes: oxidative signaling after the loss of the ability of the mitochondrial inner membrane to undergo fusion and lactic acidosis after the loss of outer membrane fusion. Finally, experiments in cultured mammalian cells demonstrate a conserved link between mitochondrial morphology and cell pH homeostasis. Taken together these data reveal a potential role for acidosis in the differing etiology of diseases associated with mitochondrial morphology defects such as ADOA and CMT-2A.
Johnson
David
D
Department of Biochemistry, Medicine, and Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA. keith_nehrke@urmc.rochester.edu
Nehrke
Keith
K
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008561:Membrane Fusion / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D034622:RNA Interference
D029742:Caenorhabditis elegans Proteins; C543815:EAT-3 protein, C elegans; C543814:FZO-1 protein, C elegans; D020558:GTP Phosphohydrolases
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