[Lesions of the mitochondrial genome and ways of its preservation].
The results of studies on damage, repair, mutation induction, and compensatory amplification of mitochondrial DNA (mtDNA) in mammalian cells are analyzed. The analysis have shown that mtDNA is a more susceptible target than nuclear DNA for endogenous and exogenous genotoxic agents, whereas DNA repair systems in mitochondria function less efficiently then in the nucleus. The rate of mutation accumulation is higher in mtDNA than in the nuclear DNA. In contrast to nuclear DNA, replication of damaged mtDNA is not blocked. MtDNA with multiple or complex lesions may be removed from mitochondria. An important mechanism of mitochondrial genome preservation is compensatory induction of new mtDNA copies. The cascade of events leading to the activation of the expression of nuclear genes controlling DNA repair in response to energy crisis is analyzed. As the key regulators of the activation of mtDNA replication and mitochondrial biogenesis, transcription coactivators PGC-1alpha and PGC-1beta are considered. These coactivators induce the expression of genes for nuclear respiratory factors NRF-1 and NRF-2. In their turn, NRF-1 and NRF-2 control the expression of mitochondrial transcription factors mtTFA, mtTFB-1, and mtTFB-2. MtTFA plays a key role not only in the mtDNA transcription regulation, but also in its stabilization and replication initiation. Thus, induction of the expression of many genes, resulting in activating mtDNA replication and increasing the number of its copies, is an important mechanism of preserving the mitochondrial genome upon the action of endogenous and exogenous damaging agents.
Gaziev
A I
AI
Shaĭkhaev
G O
GO
D000818:Animals; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D014157:Transcription Factors