Testing therapeutic strategies in MERRF: boosting mitochondrial biogenesis is not enough

Identification: Carelli, Valerio



Testing therapeutic strategies in MERRF: boosting mitochondrial biogenesis is not enough
Alessandra Maresca1, Mariantonietta Capristo1, Claudio Fiorini2, Valentina Del Dotto2, Emanuela Scimonelli2, Monica Montopoli3, Valerio Carelli1,2
1IRCCS Institute of Neurological Sciences of Bologna; 2 DIBINEM, University of Bologna; 3DSF, University of Padova
Myoclonic Epilepsy with ragged-red fibers (MERRF) is a mitochondrial encephalomyopathy due to mtDNA mutations in the MT-TK gene, the most frequent being the m.8344A>G. The pathogenic mutations affect the mitochondrial tRNALys, producing a severe defect in the mitochondrial protein synthesis that leads to impaired mitochondrial complexes activity. The MERRF mutations are always found heteroplasmic, with a high threshold for the expression of a pathologic phenotype (over 80% mutant). We used fibroblasts and cybrids carrying various m.8344A>G mutant loads to test the therapeutic potential of activated mitochondrial biogenesis, as boosted by the NAD+ donor nicotinic acid (NA). While NA was effective in increasing maximal respiration (oxygen consumption rate) and mitochondrial biogenesis (mtDNA copy number and mitochondrial protein expression) in controls and cells carrying intermediate loads of MERRF mutation, this strategy was ultimately ineffective in compensating the oxidative phosphorylation defect in cells with high mutant load (over 80%). There were some differences between fibroblasts and cybrids: while in fibroblasts the increased mtDNA copy number failed to translate into a clear increase in mitochondrial protein expression, in cybrids there was a more stringent correlation between mtDNA content and amount of OXPHOS respiratory complexes, which however was not effective in improving respiration. Interestingly, we noted the paradoxical inverse correlation of increased mtDNA copy number and decreased TFAM content after activation of mitochondrial biogenesis by NA in both cell models. Thus, the simple paradigm postulated in recent papers that activation of mitochondrial biogenesis might be a successful therapeutic strategy in mouse models of nuclear encoded mitochondrial diseases, it seems less clear in a model of a severe mtDNA heteroplasmic mutation such as the MERRF m.8344A>G. Our results suggest that high pathogenic mutant loads of this mutation hamper the compensatory efficacy of activated mitochondrial biogenesis.



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