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000136764 0247_ $$2doi$$a10.1007/s00401-012-1036-y
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000136764 037__ $$aDZNE-2020-03086
000136764 041__ $$aEnglish
000136764 082__ $$a610
000136764 1001_ $$0P:(DE-2719)2000035$$aVielhaber, Stefan$$b0$$eFirst author$$udzne
000136764 245__ $$aMitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion.
000136764 260__ $$aHeidelberg$$bSpringer$$c2013
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000136764 520__ $$aCharcot-Marie-Tooth neuropathy type 2A (CMT2A) is associated with heterozygous mutations in the mitochondrial protein mitofusin 2 (Mfn2) that is intimately involved with the outer mitochondrial membrane fusion machinery. The precise consequences of these mutations on oxidative phosphorylation are still a matter of dispute. Here, we investigate the functional effects of MFN2 mutations in skeletal muscle and cultured fibroblasts of four CMT2A patients applying high-resolution respirometry. While maximal activities of respiration of saponin-permeabilized muscle fibers and digitonin-permeabilized fibroblasts were only slightly affected by the MFN2 mutations, the sensitivity of active state oxygen consumption to azide, a cytochrome c oxidase (COX) inhibitor, was increased. The observed dysfunction of the mitochondrial respiratory chain can be explained by a twofold decrease in mitochondrial DNA (mtDNA) copy numbers. The only patient without detectable alterations of respiratory chain in skeletal muscle also had a normal mtDNA copy number. We detected higher levels of mtDNA deletions in CMT2A patients, which were more pronounced in the patient without mtDNA depletion. Detailed analysis of mtDNA deletion breakpoints showed that many deleted molecules were lacking essential parts of mtDNA required for replication. This is in line with the lack of clonal expansion for the majority of observed mtDNA deletions. In contrast to the copy number reduction, deletions are unlikely to contribute to the detected respiratory impairment because of their minor overall amounts in the patients. Taken together, our findings corroborate the hypothesis that MFN2 mutations alter mitochondrial oxidative phosphorylation by affecting mtDNA replication.
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000136764 542__ $$2Crossref$$i2012-08-28$$uhttp://www.springer.com/tdm
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000136764 650_7 $$2NLM Chemicals$$aDNA, Mitochondrial
000136764 650_7 $$2NLM Chemicals$$aMitochondrial Proteins
000136764 650_7 $$0EC 1.3.99.1$$2NLM Chemicals$$aSuccinate Dehydrogenase
000136764 650_7 $$0EC 1.9.3.1$$2NLM Chemicals$$aElectron Transport Complex IV
000136764 650_7 $$0EC 2.3.3.1$$2NLM Chemicals$$aCitrate (si)-Synthase
000136764 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aGTP Phosphohydrolases
000136764 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aMFN2 protein, human
000136764 650_2 $$2MeSH$$aAdult
000136764 650_2 $$2MeSH$$aBlotting, Western
000136764 650_2 $$2MeSH$$aCell Separation
000136764 650_2 $$2MeSH$$aCells, Cultured
000136764 650_2 $$2MeSH$$aCharcot-Marie-Tooth Disease: genetics
000136764 650_2 $$2MeSH$$aCitrate (si)-Synthase: metabolism
000136764 650_2 $$2MeSH$$aDNA Repair
000136764 650_2 $$2MeSH$$aDNA, Mitochondrial: physiology
000136764 650_2 $$2MeSH$$aElectron Transport: genetics
000136764 650_2 $$2MeSH$$aElectron Transport: physiology
000136764 650_2 $$2MeSH$$aElectron Transport Complex IV: metabolism
000136764 650_2 $$2MeSH$$aFemale
000136764 650_2 $$2MeSH$$aFibroblasts: physiology
000136764 650_2 $$2MeSH$$aGTP Phosphohydrolases: genetics
000136764 650_2 $$2MeSH$$aGene Dosage
000136764 650_2 $$2MeSH$$aHumans
000136764 650_2 $$2MeSH$$aMale
000136764 650_2 $$2MeSH$$aMicroscopy, Electron
000136764 650_2 $$2MeSH$$aMitochondria: genetics
000136764 650_2 $$2MeSH$$aMitochondria: physiology
000136764 650_2 $$2MeSH$$aMitochondrial Proteins: genetics
000136764 650_2 $$2MeSH$$aMuscle Fibers, Skeletal: physiology
000136764 650_2 $$2MeSH$$aMuscle, Skeletal: physiology
000136764 650_2 $$2MeSH$$aMutation: genetics
000136764 650_2 $$2MeSH$$aOxygen Consumption: physiology
000136764 650_2 $$2MeSH$$aSuccinate Dehydrogenase: metabolism
000136764 650_2 $$2MeSH$$aYoung Adult
000136764 7001_ $$0P:(DE-2719)9000903$$aDebska-Vielhaber, Grazyna$$b1$$eFirst author$$udzne
000136764 7001_ $$0P:(DE-HGF)0$$aPeeva, Viktoriya$$b2
000136764 7001_ $$0P:(DE-HGF)0$$aSchoeler, Susanne$$b3
000136764 7001_ $$0P:(DE-HGF)0$$aKudin, Alexei P$$b4
000136764 7001_ $$0P:(DE-2719)9000215$$aMinin, Irina$$b5$$udzne
000136764 7001_ $$0P:(DE-2719)2812631$$aSchreiber, Stefanie$$b6$$udzne
000136764 7001_ $$0P:(DE-HGF)0$$aDengler, Reinhard$$b7
000136764 7001_ $$0P:(DE-HGF)0$$aKollewe, Katja$$b8
000136764 7001_ $$0P:(DE-HGF)0$$aZuschratter, Werner$$b9
000136764 7001_ $$0P:(DE-HGF)0$$aKornblum, Cornelia$$b10
000136764 7001_ $$0P:(DE-HGF)0$$aZsurka, Gábor$$b11
000136764 7001_ $$0P:(DE-HGF)0$$aKunz, Wolfram S$$b12$$eCorresponding author
000136764 77318 $$2Crossref$$3journal-article$$a10.1007/s00401-012-1036-y$$b : Springer Science and Business Media LLC, 2012-08-28$$n2$$p245-256$$tActa Neuropathologica$$v125$$x0001-6322$$y2012
000136764 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-012-1036-y$$gVol. 125, no. 2, p. 245 - 256$$n2$$p245-256$$q125:2<245 - 256$$tActa neuropathologica$$v125$$x0001-6322$$y2013
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