Coordinate induction of energy gene expression in tissues of mitochondrialdisease patients

We have examined the transcript levels of a variety of oxidative phosphoryl ation (OXPHOS) and associated bioenergetic genes in tissues of a patient ca rrying the myopathy, encephalopathy, lactic acidosis, and strokelike episod es (MELAS) A3243G mitochondrial DNA (mtDNA) mutation and the skeletal muscl es of 14 patients harboring other pathogenic mtDNA mutations. The patients' tissues, which harbored 88% or more mutant mtDNA, had increased levels of mtDNA transcripts, increased nuclear OXPHOS gene transcripts including the ATP synthase beta subunit and the heart-muscle isoform of the adenine nucle otide translocator, and increased ancillary gene transcripts including musc le mitochondrial creatine phosphokinase, muscle glycogen phosphorylase, hex okinase I, muscle phosphofructokinase, the E1 alpha subunit of pyruvate deh ydrogenase, and the ubiquinone oxidoreductase. A similar coordinate inducti on of bioenergetic genes was observed in the muscle biopsies of severe path ologic mtDNA mutations. The more significant coordinated expression was fou nd in muscle from patients with the MELAS, myoclonic epilepsy with ragged r ed fibers, and chronic progressive external ophthalmoplegia deletion syndro mes, with ragged red muscle fibers and mitochondrial paracrystalline inclus ions. High levels of mutant mtDNAs were linked to a high induction of the m tDNA and nuclear OXPHOS genes and of several associated bioenergetic genes. These observations suggest that human tissues attempt to compensate for OX PHOS defects associated with mtDNA mutations by stimulating mitochondrial b iogenesis, possibly mediated through redox-sensitive transcription factors.