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Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption

McKenzie, M; Liolitsa, D; Akinshina, N; Campanella, M; Sisodiya, S; Hargreaves, I; Nirmalananthan, N; ... Duchen, MR; + view all (2007) Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption. J BIOL CHEM , 282 (51) 36845 - 36852. 10.1074/jbc.M704158200. Gold open access

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 (Delta psi(m)) 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 Delta psi(m) 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 Delta psi(m). 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 Delta psi(m), representing a potential pathophysiological mechanism in human mitochondrial disease.

Type: Article
Title: Mitochondrial ND5 gene variation associated with encephalomyopathy and mitochondrial ATP consumption
Open access status: An open access publication
DOI: 10.1074/jbc.M704158200
Keywords: HEREDITARY OPTIC NEUROPATHY, STROKE-LIKE EPISODES, DNA MUTATION, LACTIC-ACIDOSIS, MELAS, DISEASE, ENCEPHALOPATHY, IDENTIFICATION, FIBROBLASTS, RESPIRATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/140007
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