Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance

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.

Analysis of Human Mitochondrial DNA Content by Southern Blotting and Nonradioactive Probe Hybridization

“…Another study investigated HIV‐positive patients who developed neuropathy 6‐10 weeks after starting zalcitabine, and this investigation found mitochondrial alterations and significantly reduced mtDNA copy number in nerve biopsy samples (Dalakas, Semino‐Mora, & Leon‐Monzon, ). Additionally, cell culture, animal model, and biochemical studies have demonstrated that mitochondrial toxicity can result from NRTIs blocking the mtDNA replication and repair machinery (Young, ). Recently, Southern blotting served as a powerful tool to characterize and identify the human degradosome, the mitochondrial machinery that quickly degrades mtDNA harboring double‐stranded breaks (Peeva et al., ).…”

“…Evidence supports that mitochondria are targeted by environmental toxicants that disrupt mtDNA maintenance, and that chemical exposures can cause an increase or decrease in mtDNA copy number (Meyer et al., ). mtDNA depletion can be a side effect in human immunodeficiency virus (HIV)–infected subjects treated with nucleoside reverse transcriptase inhibitors (NRTIs; Young, ). Mitochondrial toxicity from NRTIs mimics phenotypes of mitochondrial disease, such as mitochondrial myopathy, or other clinical manifestations (Koczor & Lewis, ).…”

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

“…This hypothesis stems from the evidence that NRTIs inhibit HIV-1 reverse transcriptase as well as eukaryotic pol-γ (the mtDNA replicase that also possesses reverse transcriptase activity) [155]. In the early times of HIV epidemic, NRTIs, including azidothymidine (AZT), didanosine (ddI), and abacavir (ABC) [156-160] were proven to be able to reduce telomerase activity and TL in vitro.…”

HIV‐1, HAART and cancer: A complex relationship

“…121,155 Though at first nucleoside reverse transcriptase inhibitors (NRTIs) were supposed to be genotoxic, mutagenic and oncogenic due to their ability to incorporate into nuclear DNA and directly inhibit cellular DNA polymerases, 114,117,156,157 the subsequent clinical studies have shown no clear correlation between NRTIs and cancer (see above). In fact, in vitro studies have shown, that NRTIs might also possess anticancer activity, [158][159][160] which is probably associated with their capacity to inhibit DNA repair, 161 induce mitochondrial toxicity, 162 apoptosis, modulate activity and expression of endogenous reverse transcriptase encoded by the long interspersed nuclear element-1 (LINE-1). 158 LINE-1 propagation throughout the DNA may play a role in genome instability, mutagenesis and contribute to carcinogenesis.…”