title: Mitochondrial regulation of epigenetics and its role in human diseases.
abstract: Most pathogenic mitochondrial DNA (mtDNA) mutations induce defects in mitochondrial oxidative phosphorylation (OXPHOS). However, phenotypic effects of these mutations show a large degree of variation depending on the tissue affected. These differences are difficult to reconcile with OXPHOS as the sole pathogenic factor suggesting that additional mechanisms contribute to lack of genotype and clinical phenotype correlationship. An increasing number of studies have identified a possible effect on the epigenetic landscape of the nuclear genome as a consequence of mitochondrial dysfunction. In particular, these studies demonstrate reversible or irreversible changes in genomic DNA methylation profiles of the nuclear genome. Here we review how mitochondria damage checkpoint (mitocheckpoint) induces epigenetic changes in the nucleus. Persistent pathogenic mutations in mtDNA may also lead to epigenetic changes causing genomic instability in the nuclear genome. We propose that "mitocheckpoint" mediated epigenetic and genetic changes may play key roles in phenotypic variation related to mitochondrial diseases or host of human diseases in which mitochondrial defect plays a primary role.
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Institute for Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. sheroy@sund.ku.dk
authors.forename: Sheroy
authors.initials: S
authors.lastname: Minocherhomji
authors.forename: Trygve O
authors.initials: TO
authors.lastname: Tollefsbol
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
mesh_terms: D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial; D042822:Genomic Instability; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial