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 gamma, 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.

Automated summary

Human mitochondrial DNA (mtDNA) is a circular double-stranded DNA, responsible for encoding subunits of the electron transfer chain and essential RNAs for mitochondrial protein translation. The minimal mtDNA replisome consists of Twinkle, DNA polymerase gamma, and mitochondrial single-stranded DNA-binding protein. Both mitochondrial RNA transcription and DNA replication machineries are intertwined and regulate mtDNA copy numbers, cellular energy supplies, and cellular metabolism. This review focuses on the structural aspects of the mechanisms governing these pathways, and the mtDNA diseases caused by mutations in transcription and replication machineries. Additionally, it discusses the adverse effects of antiviral drugs on mitochondrial DNA and RNA polymerases, as well as potential structural approaches for developing less toxic nucleoside reverse transcriptase inhibitors and ribonucleoside analogs.