title: Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues.
abstract: OBJECTIVE
  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 beta-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-beta-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.
authors.affiliation: Inserm, U680, Paris, 75012 France. caron@st-antoine.inserm.fr
authors.forename: Martine
authors.initials: M
authors.lastname: Caron
authors.forename: Martine
authors.initials: M
authors.lastname: Auclairt
authors.forename: Anais
authors.initials: A
authors.lastname: Vissian
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives*
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D018894:Reverse Transcriptase Inhibitors; D013936:Thymidine