Mitochondrial DNA Replication in Health and Disease

Abstract

Mitochondria are dynamic, semi-autonomous organelles that play a diverse role in cellular physiopathology, being involved in bioenergetics, ROS generation/signaling and redox balance, β-oxidation of free fatty acids, Ca2+ homeostasis, thermogenesis, and essential anabolic pathways (fatty acids, cholesterol, urea, haem and bile acids). They contain their own, mitochondrial DNA (mtDNA) which is one of the main points in favor of the hypothesis of the endosymbiotic origin of these organelles (Lang et al., 1999). The human mitochondrial genome, a 16.5 kb circular DNA consisting of a heavy and a light chain, contains 37 genes, 13 of which encode proteins involved in the mitochondrial electron transport chain (ETC), 22 of which encode transfer RNA and the remaining 2 genes encode ribosomal RNA. A mammalian somatic cell contains between 1000 and 10000 copies of mtDNA arranged in covalently closed circular molecules. There are considerable physiological variations in the mtDNA content in any given human tissue, however the mechanism of these modulations and their clinical relevance are still not clear. Like bacterial chromosomal DNA, mtDNA is organized in DNAprotein structures called nucleoids. Several proteins seem to be involved in the maintenance of these structures. The most widely studied is Transcription Factor A (TFAM) which has a clear structural role and is necessary for nucleoid stabilization.