Antiretroviral Therapy-Induced Mitochondrial Toxicity: Potential Mechanisms Beyond Polymerase-γ Inhibition

We hypothesized that competition between nucleotide reverse‐transcriptase inhibitor triphosphate and endogenous deoxyribonucleotide triphosphate (dNTP) may lead to depletion of dNTP pools and mitochondrial dysfunction independent of polymerase‐γ (pol‐γ) inhibition. We collected peripheral blood mononuclear cells from 75 adults (25 cases: HIV‐infected patients with mitochondrial toxicity, 25 HIV‐infected positive controls, and 25 HIV‐negative controls). We observed statistically significant individual and group differences in ribonucleotide (RN) and deoxyribonucleotide (dRN) pools. The median values for the RN pools were 10,062 (interquartile range (IQR): 7,090–12,590), 4,360 (IQR: 3,058–6,838), and 2,968 (IQR: 2,538–4,436) pmol/106 cells for negative controls, positive controls, and cases, respectively. Cases had significantly higher absolute mitochondrial DNA copy number as compared with negative controls (P < 0.05). Moreover, cases had significantly higher expression levels of pol‐γ, nucleotide transporters, cellular kinases, and adenosine triphosphate (ATP)–binding cassette (ABC) proteins as compared with controls. Antiretroviral therapy (ART) perturbs RN and dRN pools. Depletion of RN and dRN pools may be associated with ART‐induced mitochondrial toxicity independent of pol‐γ inhibition.

• Publication year

  2014

• Venue

  Clinical pharmacology and therapy

• Publication date

  2014-03-17

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/clpt.2014.64PMID 24637942PMCID 4065195
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Stretchable self-tuning MRI receive coils based on liquid metal technology (LiquiTune)

  2021cited by this paper
• Mycobacterium Avium Meningitis in HIV Patients in North India

  2013cited by this paper
• Tenofovir Renal Proximal Tubular Toxicity Is Regulated By OAT1 and MRP4 Transporters

  2011cited by this paper
• Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition.

  2011cited by this paper
• Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique.

  2011cited by this paper
• Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229

  2010cited by this paper
• Inhibition of mitochondrial function by efavirenz increases lipid content in hepatic cells

  2010cited by this paper
• Enhanced oxidative stress and increased mitochondrial mass during Efavirenz‐induced apoptosis in human hepatic cells

  2010cited by this paper
• HIV protease inhibitors elicit volume-sensitive Cl- current in cardiac myocytes via mitochondrial ROS.

  2010cited by this paper
• Gene expression and immunohistochemistry in adipose tissue of HIV type 1-infected patients with nucleoside analogue reverse-transcriptase inhibitor-associated lipoatrophy.

  2009cited by this paper
• Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity

  2009cited by this paper
• Transport of nucleoside analogs across the plasma membrane: a clue to understanding drug-induced cytotoxicity.

  2009cited by this paper
• Simultaneous analysis of eight nucleoside triphosphates in cell lines by liquid chromatography coupled with tandem mass spectrometry.

  2009cited by this paper
• Distinct mechanisms for mitochondrial DNA loss in T and B lymphocytes from HIV-infected patients exposed to nucleoside reverse-transcriptase inhibitors and those naive to antiretroviral treatment.

  2008cited by this paper
• Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices

  2008cited by this paper
• Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection

  2008cited by this paper
• Increased mtDNA Levels Without Change in Mitochondrial Enzymes in Peripheral Blood Mononuclear Cells of Infants Born to HIV-Infected Mothers on Antiretroviral Therapy

  2008cited by this paper
• A brief overview of mechanisms of mitochondrial toxicity from NRTIs

  2007cited by this paper
• Some HIV Antiretrovirals Increase Oxidative Stress and Alter Chemokine, Cytokine or Adiponectin Production in Human Adipocytes and Macrophages

  2007cited by this paper
• Review of recent studies on resistance to cytotoxic deoxynucleoside analogues.

  2007cited by this paper
• Altered Expression of Nucleoside Transporter Genes (SLC28 and SLC29) in Adipose Tissue from HIV-1–Infected Patients

  2007cited by this paper
• Expression of Adenosine Triphosphate-Binding Cassette (ABC) Drug Transporters in Peripheral Blood Cells

  2007cited by this paper
• Uridine Supplementation for the treatment of Antiretroviral Therapy-Associated Lipoatrophy: A Randomized, Double-Blind, Placebo-Controlled Trial

  2007cited by this paper
• Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity.

  2006cited by this paper
• Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society--USA panel.

  2006cited by this paper
• Expression of MDR1 in epithelial ovarian cancer and its association with disease progression.

  2006cited by this paper
• Tissue-Specific Associations Between Mitochondrial DNA Levels and Current Treatment Status in HIV-Infected Individuals

  2006cited by this paper
• Possible Ways Nucleoside Analogues Can Affect Mitochondrial Dna Content and Gene Expression during HIV Therapy

  2005cited by this paper
• Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine

  2005cited by this paper
• Mitochondrial (Mt)Dna Changes in Tissue May Not be Reflected by Depletion of Mtdna in Peripheral Blood Mononuclear Cells in HIV-Infected Patients

  2005cited by this paper
• Mitochondrial Dna Levels of Peripheral Blood Mononuclear Cells and Subcutaneous Adipose Tissue from Thigh, Fat and Abdomen of HIV-1 Seropositive and Negative Individuals

  2005cited by this paper
• In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA.

  2005cited by this paper
• Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo

  2005cited by this paper
• Changes in Mitochondrial Rna Production in Cells Treated with Nucleoside Analogues

  2005cited by this paper
• Tissue distribution and disease manifestations of the tRNALys A»G(8344) mitochondrial DNA mutation in a case of myoclonus epilepsy and ragged red fibres

  2004cited by this paper
• Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel.

  2004cited by this paper
• Assessment of precision and concordance of quantitative mitochondrial DNA assays: a collaborative international quality assurance study.

  2003cited by this paper
• ATP-binding cassette superfamily transporter gene expression in human primary ovarian carcinoma.

  2002cited by this paper
• Long‐term Exposure to Lifelong Therapies

  2002cited by this paper
• Increased Replication of Non-Syncytium-Inducing HIV Type 1 Isolates in Monocyte-Derived Macrophages Is Linked to Advanced Disease in Infected Children

  2002cited by this paper
• Analysis of the mitochondrial DNA genome in the peripheral blood leukocytes of HIV-infected patients with or without lipoatrophy

  2002cited by this paper
• Adverse effects of medications and trade-offs between length of life and quality of life in human immunodeficiency virus infection.

  2002cited by this paper
• Phosphorylation of nucleosides and nucleoside analogs by mammalian nucleoside monophosphate kinases.

  2000cited by this paper
• Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity.

  2000cited by this paper
• Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.

  1999cited by this paper
• Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.

  1999cited by this paper
• Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway

  1998cited by this paper
• Differential incorporation of ara-C, gemcitabine, and fludarabine into replicating and repairing DNA in proliferating human leukemia cells.

  1997cited by this paper
• Mitochondrial toxicity of antiviral drugs

  1995cited by this paper
• Deoxynucleotide pools and DNA synthesis in resting and PHA-stimulated human lymphocytes treated with mutagens.

  1992cited by this paper
• Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity.

  1991cited by this paper
• Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2',3'-dideoxycytidine.

  1989cited by this paper

• Pioglitazone Modulates p65-Mediated Mitochondrial Bioenergetics: Implications for Acetaldehyde-Induced HIV Replication in Alveolar Macrophages

  2025cites this paper
• Narrative Review on the Management of Neck of Femur Fractures in People Living with HIV: Challenges, Complications, and Long-Term Outcomes

  2025cites this paper
• Mitochondrial Dysfunction in Aging, HIV, and Long COVID: Mechanisms and Therapeutic Opportunities

  2025cites this paper
• Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Induced Neuropathy and Mitochondrial Toxicity: Limitations of the Poly-γ Hypothesis and the Potential Roles of Autophagy and Drug Transport

  2024influential citation
• Ptosis in human immunodeficiency virus-infected patients under long-term antiretroviral treatment.

  2024cites this paper
• Distinct profile of antiviral drugs effects in aortic and pulmonary endothelial cells revealed by high-content microscopy and cell painting assays.

  2024cites this paper
• Connection Between HIV and Mitochondria in Cardiovascular Disease and Implications for Treatments

  2024cites this paper
• Mitochondrial DNA and Electron Transport Chain Protein Levels Are Altered in Peripheral Nerve Tissues from Donors with HIV Sensory Neuropathy: A Pilot Study

  2024cites this paper
• Sarcopenia risk, sarcopenia-related quality of life, and associated factors in people living with human immunodeficiency virus (HIV): A web-based survey.

  2024cites this paper
• HIV-exposed uninfected infants’ immune defects: From pathogen sensing, oxidative burst to antigens responses

  2023cites this paper
• A Step Closer to the “Fourth 90”: A Practical Narrative Review of Diagnosis and Management of Nutritional Issues of People Living with HIV

  2021cites this paper
• Substance Use, Highly Active Antiretroviral Therapy, and Liver Enzymes: Evidence From a Cross-Sectional Study of HIV-Infected Adult Patients Without Comorbidities on HAART in the University of Port Harcourt Teaching Hospital

  2021cites this paper
• Mitochondrial changes associated with viral infectious diseases in the paediatric population

  2021cites this paper
• HIV Infection and Related Mental Disorders

  2021cites this paper
• Dysfunctional Immunometabolism in HIV Infection: Contributing Factors and Implications for Age-Related Comorbid Diseases

  2020cites this paper
• The Level of Cytokeratin 18 in Patients with HIV and Viral Hepatitis C Co-Infection in Latvia

  2020cites this paper
• Plasticity in T-cell mitochondrial metabolism: A necessary peacekeeper during the troubled times of persistent HIV-1 infection.

  2020cites this paper
• Identifying the role of PrimPol in TDF-induced toxicity and implications of its loss of function mutation in an HIV+ patient

  2020cites this paper
• Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine

  2020cites this paper
• Pharmacotherapeutic options for kidney disease in HIV positive patients

  2020cites this paper
• A comparison of machine learning techniques for classification of HIV patients with antiretroviral therapy-induced mitochondrial toxicity from those without mitochondrial toxicity

  2019cites this paper
• Dysregulation of sterol regulatory element-binding protein 2 gene in HIV treatment-experienced individuals

  2019cites this paper
• Provision of combined antiretroviral therapy in HIV-positive pregnant women and the increased risk of apoptosis-related intra-uterine growth restriction

  2019cites this paper
• Nucleoside/nucleotide reverse transcriptase inhibitors attenuate angiogenesis and lymphangiogenesis by impairing receptor tyrosine kinases signalling in endothelial cells

  2018cites this paper
• Myoblast mitochondrial respiration is decreased in chronic binge alcohol administered simian immunodeficiency virus‐infected antiretroviral‐treated rhesus macaques

  2018cites this paper
• Changing concepts of HIV infection and renal disease

  2018cites this paper
• Pharmacogenetic variation influences sensory neuropathy occurrence in Southern Africans treated with stavudine-containing antiretroviral therapy

  2018cites this paper
• Skeletal Muscle Mitochondrial Toxicity

  2018cites this paper
• Comparison of low and high DNA Purity for quantitative detection of ratio Mitochondrial and Nucleus DNA among Drug-treated HIV Patients by Real-time PCR

  2018cites this paper
• Does oxidative stress contribute to adverse outcomes in HIV-associated TB?

  2018cites this paper
• Mitochondrial profile and amyloidogenic molecules in sporadic inclusion body myositis

  2017influential citation
• Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration

  2017cites this paper
• Modulation of Lipid Droplet Metabolism—A Potential Target for Therapeutic Intervention in Flaviviridae Infections

  2017cites this paper
• High frequency of mitochondrial DNA mutations in HIV‐infected treatment‐experienced individuals

  2016cites this paper
• Toxicology Strategies for Drug Discovery: Present and Future.

  2016cites this paper
• The DNA Polymerase Gamma R953C Mutant Is Associated with Antiretroviral Therapy-Induced Mitochondrial Toxicity

  2016cites this paper
• HIV‐1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion

  2016cites this paper
• Association of circulating cytochrome c with clinical manifestations of antiretroviral-induced toxicity.

  2015cites this paper
• The search for nucleoside/nucleotide analog inhibitors of dengue virus.

  2015cites this paper
• Prevalence, underlying mechanisms and role of nutrition in the management of the HIV-associated lipodystrophy syndrome

  2015cites this paper
• Antiretroviral therapy–induced toxicity is associated with increased mRNA expression of telomerase

  2015cites this paper
• Is the atherosclerotic process accentuated under conditions of HIV infection, antiretroviral therapy, and protease inhibitor exposure? Meta-analysis of the markers of arterial structure and function.

  2015cites this paper
• Thymidine kinase 2 enzyme kinetics elucidate the mechanism of thymidine-induced mitochondrial DNA depletion.

  2014cites this paper
• Zidovudine Induces Downregulation of Mitochondrial Deoxynucleoside Kinases: Implications for Mitochondrial Toxicity of Antiviral Nucleoside Analogs

  2014cites this paper