Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

Abstract

We have examined the transcript levels of a variety of oxidative phosphorylation (OXPHOS) and associated bioenergetic genes in tissues of a patient carrying the myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) A3243G mitochondrial DNA (mtDNA) mutation and the skeletal muscles 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 ␤ subunit and the heart-muscle isoform of the adenine nucleotide translocator, and increased ancillary gene transcripts including muscle mitochondrial creatine phosphokinase, muscle glycogen phosphorylase, hexokinase I, muscle phosphofructokinase, the E1␣ subunit of pyruvate dehydrogenase, and the ubiquinone oxidoreductase. A similar coordinate induction of bioenergetic genes was observed in the muscle biopsies of severe pathologic mtDNA mutations. The more significant coordinated expression was found in muscle from patients with the MELAS, myoclonic epilepsy with ragged red fibers, and chronic progressive external ophthalmoplegia deletion syndromes, with ragged red muscle fibers and mitochondrial paracrystalline inclusions. High levels of mutant mtDNAs were linked to a high induction of the mtDNA and nuclear OXPHOS genes and of several associated bioenergetic genes. These observations suggest that human tissues attempt to compensate for OXPHOS defects associated with mtDNA mutations by stimulating mitochondrial biogenesis, possibly mediated through redox-sensitive transcription factors.

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

“…These findings contrast with observations in budding yeast cells where respiratory chain deficiency is followed by induced expression of genes that encode peroxisomal enzymes (6). In a previous study it was found that patients with different mtDNA mutations and rearrangements have an increased expression of genes encoding glycolytic enzymes in affected tissues (32). We found that the glycolytic enzyme activities do not directly correlate with the altered levels of gene expression, suggesting that there are posttranscriptional regulatory events involved.…”

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

“…As usually occurs in mitochondrial disorders, the mtDNA depletion is associated with marked mitochondrial proliferation, a well known compensatory strategy for the reduced respiratory chain function. 18 The mtDNA depletion involves the muscularis propria of the entire GI tract and is most dramatically prominent in its external layer. In stomach and small intestine, the profound mtDNA depletion at this site correlates well with the observed atrophy and interstitial fibrosis.…”

Natural variation of the Y chromosome suppresses sex ratio distortion and modulates testis-specific gene expression in Drosophila simulans

“…U p r e g u l a t i o n i n r e s i s t a n t s t r a i n s D o w n r e g u l a t i o n i n r e s i s t a n t s t r a i n s regulation of genes associated with ATP biosynthesis might point to inefficiencies of the energetic metabolism due to the mitochondrial degeneration in the Y-bearing spermatids that lead the upregulation of bioenergetic genes to compensate the energetic needs of the 'ill' cell (Heddi et al, 1999;Epstein et al, 2001). Altogether, the data support the notion that maternally and paternally inherited elements might genetically interact in the etiology of sex ratio distortion.…”