Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs used to treat human immunodeficiency virus (HIV) the cause of acquired immunodeficiency syndrome. Development of severe mitochondrial toxicity has been well documented in patients infected with HIV and administered NRTIs. In vitro biochemical experiments have demonstrated that the replicative mitochondrial DNA (mtDNA) polymerase gamma, Polg, is a sensitive target for inhibition by metabolically active forms of NRTIs, nucleotide reverse transcriptase inhibitors (NtRTIs). Once incorporated into newly synthesized daughter strands NtRTIs block further DNA polymerization reactions. Human cell culture and animal studies have demonstrated that cell lines and mice exposed to NRTIs display mtDNA depletion. Further complicating NRTI off-target effects on mtDNA maintenance, two additional DNA polymerases, Pol beta and PrimPol, were recently reported to localize to mitochondria as well as the nucleus. Similar to Polg, in vitro work has demonstrated both Pol beta and PrimPol incorporate NtRTIs into nascent DNA. Cell culture and biochemical experiments have also demonstrated that antiviral ribonucleoside drugs developed to treat hepatitis C infection act as off-target substrates for POLRMT, the mitochondrial RNA polymerase and primase. Accompanying the above-mentioned topics, this review examines: (1) mtDNA maintenance in human health and disease, (2) reports of DNA polymerases theta and zeta (Rev3) localizing to mitochondria, and (3) additional drugs with off-target effects on mitochondrial function. Lastly, mtDNA damage may induce cell death; therefore, the possibility of utilizing compounds that disrupt mtDNA maintenance to kill cancer cells is discussed.
Highlights
In vitro biochemical experiments have demonstrated that the replicative mitochondrial DNA polymerase gamma, Polg, is a sensitive target for inhibition by metabolically active forms of Nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs)
This study demonstrated that toxic effects of antiviral ribonucleosides (AVRNs) might result from inhibition of the mitochondrial transcription machinery and mitochondrial DNA (mtDNA) gene expression (Arnold et al, 2012a)
Gene variations may exacerbate mitochondrial diseaselike phenotypes in human immunodeficiency virus (HIV)-infected patients treated with NRTIs
Summary
The haploid human nuclear genome consists of ∼3 billion base pairs (bp) of DNA and contains ∼20,000 protein-coding genes and ∼23,000 non-coding genes. The mitochondrial genome harbors only 13 genes for polypeptides, 2 genes for rRNA, and 22 genes for tRNA on ∼16,600 bp and mutations associated with maternally-inherited mitochondrial disorders have been identified in all 37 open reading frames. While the size and coding capacity of mtDNA is much less than the nuclear genome our maternally inherited genome is critical to cellular viability as exemplified by the numerous disease mutations associated with it and by observations that knocking out mtDNA maintenance genes results in embryonic lethality in various mouse models (Park and Larsson, 2011). Nuclear-encoded mitochondrial ribosomal subunits assemble with mtDNAencoded rRNAs following protein import to form the translation machinery necessary to synthesize the 13 mtDNA-encoded polypeptides. The MIM OXPHOS energy-generating process is strictly dependent on mtDNA maintenance and pharmacological blocks to mitochondrial genome replication would be devastating to this energy-generating process
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