Introduction of an additional pathway for lactate oxidation in the treatment of lactic acidosis and mitochondrial dysfunction in Caenorhabditis elegans.
Mitochondrial dysfunction, with an estimated incidence of 1 in 5,000 births, is associated with a wide variety of multisystem degenerative diseases. Among the most prevalent forms of dysfunction are defects in the NADH:ubiquinone oxidoreductase (complex I). Caenorhabditis elegans strains with complex I mutations exhibit characteristic features of human mitochondrial disease including decreased rates of respiration and lactic acidosis. We hypothesized that introducing an additional pathway for the direct oxidation of lactate would be beneficial for energy metabolism. The yeast CYB2 gene encodes an L-lactate:cytochrome c oxidoreductase that oxidizes lactate, donates electrons directly into the mitochondrial respiratory chain, and supports lactate-dependent respiration. Cyb2p expression markedly increases lifespan, fertility, respiration rates, and ATP content in complex I-deficient animals. Our results indicate that metabolic imbalance leading to lactic acidosis and energy depletion are central mechanisms of pathogenesis in mitochondrial dysfunction and that introduction of an additional pathway for lactate oxidation should be considered as a treatment.
Grad
Leslie I
LI
Department of Biochemistry, University of Alberta, Edmonton, AB, Canada T6G 2H7.
Sayles
Leanne C
LC
Lemire
Bernard D
BD
D000140:Acidosis, Lactic / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D019344:Lactic Acid / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
D019344:Lactic Acid; D009245:NADH Dehydrogenase