Inherited mitochondrial genomic instability and chemical exposures

Abstract

There are approximately 1500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al., 2006). Each mitochondrion has its own genome (mtDNA), which in humans encodes 13 polypeptides, 22 tRNAs and 2 rRNAs required for oxidative phosphorylation. The mitochondrial genome of humans and most vertebrates is approximately 16.5kbp, double-stranded, circular, with few non-coding bases. Thus, maintaining mtDNA stability, that is, the ability of the cell to maintain adequate levels of mtDNA template for oxidative phosphorylation is essential and can be impacted by the level of mtDNA mutation currently within the cell or mitochondrion, but also from errors made during normal mtDNA replication, defects in mitochondrial quality control mechanisms, and exacerbated by exposures to exogenous and/or endogenous genotoxic agents. In this review, we expand on the origins and consequences of mtDNA instability, the current state of research regarding the mechanisms by which mtDNA instability can be overcome by cellular and chemical interventions, and the future of research and treatments for mtDNA instability.

Keywords: Disease; Gene-environment interactions; Mitochondria; Mitochondrial DNA; Therapeutics; Toxicity.