Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS

摘要: The m.3243A>G variant in the mitochondrial tRNA(Leu(UUR)) gene is a common DNA (mtDNA) mutation. Phenotypic manifestations depend mainly on heteroplasmy, i.e. ratio of mutant to normal mtDNA copies. A high percentage associated with severe, life-threatening neurological syndrome known as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). described neurovascular disorder primarily affecting brain blood vessels, but pathophysiology disease poorly understood. We developed series cybrid cell lines at two different loads: 70% 100% nuclear background neuroblastoma line (SH-SY5Y). investigated impact mutation metabolism respiratory chain activity cybrids. induced metabolic switch towards glycolysis neuronal cells produced severe defects assembly activity. used strategies compensate for biochemical cells: one consisted lowering glucose content culture medium, other involved addition l-arginine. reduction significantly shifted wild-type, reaching 90% level restoring complex assembly. l-arginine, nitric oxide (NO) donor, improved I which defective NO had led relative shortage NO. Thus, metabolically heteroplasmy shifting l-arginine therapy may constitute promising therapeutic against MELAS.