Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption

Matthew McKenzie, Danae Liolitsa, Natalya Akinshina, Michelangelo Campanella, Sanjay Sisodiya, Ian Hargreaves, Niranjanan Nirmalananthan, Mary Sweeney, Patrick Abou-Sleiman, Nicholas Wood, Michael Hanna, Michael Duchen

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56 Citations (Scopus)

Abstract

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 (Deltapsim) 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 Deltapsim were 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 Deltapsim. 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 Deltapsim, representing a potential pathophysiological mechanism in human mitochondrial disease.
Original languageEnglish
Pages (from-to)36845 - 36852
Number of pages8
JournalThe Journal of Biological Chemistry
Volume282
Issue number51
DOIs
Publication statusPublished - 2007
Externally publishedYes

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