Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity

Human mitochondrial DNA (mtDNA) is a 16.9 kbp double-stranded, circular DNA, encoding subunits of the oxidative phosphorylation electron transfer chain and essential RNAs for mitochondrial protein translation. The minimal human mtDNA replisome is composed of the DNA helicase Twinkle, DNA polymerase γ, and mitochondrial single-stranded DNA-binding protein. While the mitochondrial RNA transcription is carried out by mitochondrial RNA polymerase, mitochondrial transcription factors TFAM and TFB2M, and a transcription elongation factor, TEFM, both RNA transcriptions, and DNA replication machineries are intertwined and control mtDNA copy numbers, cellular energy supplies, and cellular metabolism. In this review, we discuss the mechanisms governing these main pathways and the mtDNA diseases that arise from mutations in transcription and replication machineries from a structural point of view. We also address the adverse effect of antiviral drugs mediated by mitochondrial DNA and RNA polymerases as well as possible structural approaches to develop nucleoside reverse transcriptase inhibitor and ribonucleosides analogs with reduced toxicity.