ArticleToxicology and applied pharmacology2008
Adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors.
Article in Toxicology and applied pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 40 citations in OpenAlex.
- The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro.Archives of toxicology · 2022Article
- A Critical Review of the Biochemical Mechanisms and Epigenetic Modifications in HIV- and Antiretroviral-Induced Metabolic Syndrome.International journal of molecular sciences · 2021Review
- Phosphorylation of OXPHOS Machinery Subunits: Functional Implications in Cell Biology and Disease.The Yale journal of biology and medicine · 2019Review
- Unraveling mechanisms of toxicant-induced oxidative stress in cardiovascular disease.Current opinion in toxicology · 2018Article
- Examining Relationships between Metabolism and Persistent Inflammation in HIV Patients on Antiretroviral Therapy.Mediators of inflammation · 2018Review
- Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity.PloS one · 2017Article
- Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.PloS one · 2015Article
- Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.Toxicological sciences : an official journal of the Society of Toxicology · 2013Article
- Role of mitochondria in HIV infection and associated metabolic disorders: focus on nonalcoholic fatty liver disease and lipodystrophy syndrome.Oxidative medicine and cellular longevity · 2013Review
- HIV-1, reactive oxygen species, and vascular complications.Free radical biology & medicine · 2012Review
- Zidovudine exposure in HIV-1 infected Tanzanian women increases mitochondrial DNA levels in placenta and umbilical cords.PloS one · 2012Article
- Hoechst 33342 induced reactive oxygen species and impaired expression of cytochrome c oxidase subunit 1 leading to cell death in irradiated human cancer cells.Molecular and cellular biochemistry · 2011Article
- AZT-induced oxidative cardiovascular toxicity: attenuation by Mg-supplementation.Cardiovascular toxicology · 2009Article
- Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism.Free radical biology & medicine · 2009Article
- The roles of HIV-1 proteins and antiretroviral drug therapy in HIV-1-associated endothelial dysfunction.Journal of investigative medicine : the official publication of the American Federation for Clinical Research · 2008Review
- Mitochondrial DNA impairment in nucleoside reverse transcriptase inhibitor-associated cardiomyopathy.Chemical research in toxicology · 2008Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Nucleoside analog reverse transcriptase inhibitors (NRTIs) are known to directly inhibit mitochondrial complex I activity as well as various mitochondrial kinases. Recent observations that complex I activity and superoxide production are modulated through cAMP-dependent phosphorylation suggests a mechanism through which NRTIs may affect mitochondrial respiration via kinase-dependent protein phosphorylation. In the current study, we examine the potential for NRTIs to inhibit the cAMP-dependent phosphorylation of complex I and the associated NADH:CoQ oxidoreductase activities and rates of superoxide production using HepG2 cells. Phosphoprotein staining of immunocaptured complex I revealed that 3'-azido-3'-deoxythymidine (AZT; 10 and 50 microM), AZT monophosphate (150 microM), and 2',3'-dideoxycytidine (ddC; 1 microM) prevented the phosphorylation of the NDUFB11 subunit of complex I. This was associated with a decrease in complex I activity with AZT and AZT monophosphate only. In the presence of succinate, superoxide production was increased with 2',3'-dideoxyinosine (ddI; 10 microM) and ddC (1 microM). In the presence of succinate+cAMP, AZT showed an inverse dose-dependent effect on superoxide production. None of the NRTIs examined inhibit PKA activity suggesting that the observed effects are due to a direct interaction with complex I. These data demonstrate a direct effect of NRTIs on cAMP-dependent regulation of mitochondrial bioenergetics independent of DNA polymerase-gamma activity; in the case of AZT, these observations may provide a mechanism for the observed long-term toxicity with this drug.
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