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CELLULAR METABOLISM

Decreased affinity for oxygen of cytochrome-c oxidase in Leigh syndrome caused by SURF1 mutations

Petr Pecina,¹ Erich Gnaiger,² Jií Zeman,³ Ewa Pronicka,⁴ and Josef Houtk¹

¹Institute of Physiology and Center for Integrated Genomics, Academy of Sciences of the Czech Republic, 142 20 Prague; ³Department of Pediatrics, 1st Medical Faculty, Charles University, 110 00 Prague, Czech Republic; ²Department of Transplant Surgery, D. Swarovski Research Laboratory, University Hospital Innsbruck, A-6020 Innsbruck, Austria; and ⁴Department of Metabolic Diseases, Children's Memorial Health Hospital, 04-730 Warsaw, Poland

Submitted 16 June 2004 ; accepted in final form 13 July 2004

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.

oxygen kinetics; mitochondrial disease

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