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Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption

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posted on 2007-12-21, 00:00 authored by Matthew McKenzieMatthew McKenzie, D Liolitsa, N Akinshina, M Campanella, S Sisodiya, I Hargreaves, N Nirmalananthan, M G Sweeney, P M Abou-Sleiman, N W Wood, M G Hanna, M R Duchen
Mitochondrial encephalomyopathy and lactic acidosis with strokelike episodes (MELAS) is a severe young onset stroke disorder without effective treatment. We have identified a MELAS patient harboring a 13528A→G mitochondrial DNA (mtDNA) mutation in the Complex I ND5 gene. This mutation was homoplasmic in mtDNA from patient muscle and nearly homoplasmic (99.9%) in blood. Fibroblasts from the patient exhibited decreased mitochondrial membrane potential (Δψm) and increased lactate production, consistent with impaired mitochondrial function. Transfer of patient mtDNA to a new nuclear background using transmitochondrial cybrid fusions confirmed the pathogenicity of the 13528A→G mutation; Complex I-linked respiration and Δψmwere both significantly reduced in patient mtDNA cybrids compared with controls. Inhibition of the adenine nucleotide translocase or the F1F0-ATPase with bongkrekic acid or oligomycin caused a loss of potential in patient mtDNA cybrid mitochondria, indicating a requirement for glycolytically generated ATP to maintain Δψm. This was confirmed by inhibition of glycolysis with 2-deoxy-D-glucose, which caused depletion of ATP and mitochondrial depolarization in patient mtDNA cybrids. These data suggest that in response to impaired respiration due to the mtDNA mutation, mitochondria consume ATP to maintain Δψm, representing a potential pathophysiological mechanism in human mitochondrial disease. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

History

Journal

Journal of Biological Chemistry

Volume

282

Issue

51

Pagination

36845 - 36852

Publisher

American Society for Biochemistry and Molecular Biology

Location

Bethesda, MD

ISSN

0021-9258

eISSN

1083-351X

Language

eng

Publication classification

CN.1 Other journal article