Decreased affinity for oxygen of cytochrome-c oxidase in Leigh syndrome caused by SURF1 mutations.
Mutations in the gene SURF1 prevent synthesis of cytochrome-c oxidase (COX)-specific assembly protein and result in a fatal neurological disorder, Leigh syndrome. Because this severe COX deficiency presents with barely detectable changes of cellular respiratory rates under normoxic conditions, we analyzed the respiratory response to low oxygen in cultured fibroblasts harboring SURF1 mutations with high-resolution respirometry. The oxygen kinetics was quantified by the partial pressure of oxygen (PO2) at half-maximal respiration rate (P50) in intact coupled cells and in digitonin-permeabilized uncoupled cells. In both cases, the P50 in patients was elevated 2.1- and 3.3-fold, respectively, indicating decreased affinity of COX for oxygen. These results suggest that at physiologically low intracellular PO2, the depressed oxygen affinity may lead in vivo to limitations of respiration, resulting in impaired energy provision in Leigh syndrome patients.
Institute of Physiology and Center for Integrated Genomics, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic.
Petr
P
Pecina
Erich
E
Gnaiger
Jirí
J
Zeman
Ewa
E
Pronicka
Josef
J
Houstek
D002478:Cells, Cultured; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003576:Electron Transport Complex IV / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007888:Leigh Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009154:Mutation; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D011506:Proteins / Q000235:genetics*
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C092928:Surf-1 protein; D003576:Electron Transport Complex IV; D010100:Oxygen