Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance
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 vi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-11-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fmolb.2017.00074/full |
| _version_ | 1818982205692575744 |
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| author | Matthew J. Young |
| author_facet | Matthew J. Young |
| author_sort | Matthew J. Young |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T17:43:31Z |
| format | Article |
| id | doaj.art-b07023249ac14e3b9bb2fe79207fb8f8 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-20T17:43:31Z |
| publishDate | 2017-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-b07023249ac14e3b9bb2fe79207fb8f82022-12-21T19:31:02ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2017-11-01410.3389/fmolb.2017.00074310428Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA MaintenanceMatthew J. YoungNucleoside 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.http://journal.frontiersin.org/article/10.3389/fmolb.2017.00074/fullnucleoside reverse transcriptase inhibitorsmitochondrial DNA polymerase gammahuman immunodeficiency virus (HIV)mitochondrial diseasescancerantiviral ribonucleosides |
| spellingShingle | Matthew J. Young Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance Frontiers in Molecular Biosciences nucleoside reverse transcriptase inhibitors mitochondrial DNA polymerase gamma human immunodeficiency virus (HIV) mitochondrial diseases cancer antiviral ribonucleosides |
| title | Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance |
| title_full | Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance |
| title_fullStr | Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance |
| title_full_unstemmed | Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance |
| title_short | Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance |
| title_sort | off target effects of drugs that disrupt human mitochondrial dna maintenance |
| topic | nucleoside reverse transcriptase inhibitors mitochondrial DNA polymerase gamma human immunodeficiency virus (HIV) mitochondrial diseases cancer antiviral ribonucleosides |
| url | http://journal.frontiersin.org/article/10.3389/fmolb.2017.00074/full |
| work_keys_str_mv | AT matthewjyoung offtargeteffectsofdrugsthatdisrupthumanmitochondrialdnamaintenance |