The addition of ketone bodies alleviates mitochondrial dysfunction by restoring complex I assembly in a MELAS cellular model

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Frey, Samuel¹  Geffroy, Guillaume¹  Desquiret-Dumas, Valerie^1,2  Gueguen, Naig^1,2  Bris, Celine^1,2  Belal, Sophie¹  Amati-Bonneau, Patrizia^1,2  Chevrollier, Arnaud¹  Barth, Magalie²  Henrion, Daniel¹  Lenaers, Guy¹  Bonneau, Dominique^1,2  Reynier, Pascal^1,2  Procaccio, Vincent^1,2 

[1] Univ Angers, INSERM U1083, Mitovasc Inst, UMR CNRS 6214, Angers, France

[2] Angers Hosp, Dept Biochem & Genet, F-49000 Angers, France

关键词: Mitochondria;    Mitochondrial diseases;    Mitochondrial DNA;    MELAS syndrome;    Complex I assembly;    Ketone bodies;   

DOI  :  10.1016/j.bbadis.2016.10.028

来源: Elsevier

【 摘 要 】

Ketogenic Diet used to treat refractory epilepsy for almost a century may represent a treatment option for mitochondrial disorders for which effective treatments are still lacking. Mitochondrial complex I deficiencies are involved in a broad spectrum of inherited diseases including Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes syndrome leading to recurrent cerebral insults resembling strokes and associated with a severe complex I deficiency caused by mitochondrial DNA (mtDNA) mutations. The analysis of MELAS neuronal cybrid cells carrying the almost homoplasmic m.3243A>G mutation revealed a metabolic switch towards glycolysis with the production of lactic acid, severe defects in respiratory chain activity and complex I disassembly with an accumulation of assembly intermediates. Metabolites, NADH/NAD(+) ratio, mitochondrial enzyme activities, oxygen consumption and BN-PAGE analysis were evaluated in mutant compared to control cells. A severe complex I enzymatic deficiency was identified associated with a major complex I disassembly with an accumulation of assembly intermediates of 400 kDa. We showed that Ketone Bodies (KB) exposure for 4 weeks associated with glucose deprivation significantly restored complex I stability and activity, increased ATP synthesis and reduced the NADH/NAD+ ratio, a key component of mitochondrial metabolism. In addition, without changing the mutant load, mtDNA copy number was significantly increased with KB, indicating that the absolute amount of wild type mtDNA copy number was higher in treated mutant cells. Therefore KB may constitute an alternative and promising therapy for MELAS syndrome, and could be beneficial for other mitochondrial diseases caused by complex I deficiency. (C) 2016 Elsevier B.V. All rights reserved.

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