Cited by 114HIV-related health complications and treatmentsMitochondrial Function and PathologyHIV/AIDS drug development and treatment

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Contribution of Mitochondrial Dysfunction and Oxidative Stress to Cellular Premature Senescence Induced by Antiretroviral Thymidine Analogues

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Caron, Martine, Auclair, Martine, Vissian, Anais, Vigouroux, Corinne, Capeau, Jacqueline·2008·Antiviral Therapy

DOI 10.1177/135965350801300103

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Abstract

Objectives: Treatment of HIV-infected patients is associated with early onset of aging-related comorbidities. Some of the adverse effects of antiretroviral therapy have been attributed to the mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI), and it is of note that mitochondrial dysfunction and oxidative stress are involved in the aging processes. In this regard, we examined whether NRTIs could accelerate the senescence of cultured cells. Methods: Human fibroblasts were exposed to NRTIs from culture passage 1 to 14. Cytochrome c-oxidase (COX) subunits 2 and 4, mitochondrial potential and mass, and reactive oxygen species (ROS) were quantified at each passage. Proliferation, cell-cycle arrest, senescence-associated β-galactosidase activity, and morphology were assessed in parallel. Mitochondrial and senescence markers were assessed in cultured murine preadipocytes and in fat samples from lipodystrophic HIV-infected patients. Results: Stavudine and zidovudine induced mitochondrial dysfunction and increased ROS levels in fibroblasts at early culture passages, while cell division gradually slowed. At passages 8–12, fibroblasts exposed to stavudine or zidovudine but not abacavir, didanosine, lamivudine and tenofovir were senescent, on the basis of p16 INK4 and p21 WAF-1 protein expression, cell morphology and senescence-associated-β-galactosidase activity. Senescence markers and COX2 underexpression were also found in 3T3-F442A preadipocytes exposed for 7 weeks to stavudine or zidovudine, but not lamivudine, and in adipose tissue samples from lipodystrophic HIV-infected patients on antiretroviral regimens containing stavudine or zidovudine. Conclusions: Mitochondrial changes and oxidative damage could partly explain the premature senescence of fibroblasts and adipose cells induced by stavudine and zidovudine. This suggests that thymidine analogues might be involved in the early aging-related diseases observed in some HIV-infected patients taking antiretroviral drugs.

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Authors: Caron, M., Auclair, M., Vissian, A., Vigouroux, C., & Capeau, J.
Affiliations: Inserm (FR)
Inserm, U680, Paris, 75012 France
ORCID: Auclair, Martine
Vigouroux, Corinne
Capeau, Jacqueline
Venue: Antiviral Therapy
Publisher: SAGE Publications
Published: 2008-01
Volume: 13
Issue: 1
Pages: 27-38
ISSN: 1359-6535 (ISSN-L)
2040-2058
DOI: 10.1177/135965350801300103
OpenAlex: W56705576
Cited by: 114
References: 50
Citations by year: 2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 3 · 2019: 10 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 10
FWCI: 12.08
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Antiviral Therapy (publishedVersion)
PubMed (publishedVersion)
Funders: Styrelsen för Internationellt Utvecklingssamarbete
Sidaction
European Commission (LSHM-CT-2005-018690, 018690)
Institut National de la Santé et de la Recherche Médicale
Topics: Health Sciences › Medicine › Infectious Diseases › HIV-related health complications and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords: mitochondrial dysfunction, oxidative stress, thymidine analogs, nucleoside reverse transcriptase inhibitors, stavudine, zidovudine, antiretroviral therapy, lipodystrophy, cytochrome c oxidase, reactive oxygen species, senescence-associated β-galactosidase, p16INK4, p21WAF-1, fibroblasts, preadipocytes, adipose tissue
MeSH terms: Adipose Tissue, Cells, Cultured, Fibroblasts, Gene Expression Regulation, Humans, Mitochondria, Thymidine, Biomarkers, HIV Infections, Cellular Senescence, Oxidative Stress, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Cell Proliferation

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Contribution of Mitochondrial Dysfunction and Oxidative Stress to Cellular Premature Senescence Induced by Antiretroviral Thymidine Analogues

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