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Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes.: Adipocyte mitochondrial toxicity of antiHIV drugs

Abstract : OBJECTIVE: To evaluate the mechanisms of mitochondrial toxicity associated with antiretroviral treatment. METHODS: 3T3-F442A white and T37i brown adipocytes were exposed to stavudine (10 microM), zidovudine (1 microM) and indinavir (10 microM), alone or in combination. Adipocyte fat content was measured with Oil Red 0 staining. Quantification of mRNA levels and of mitochondrial DNA content used PCR-based techniques. Mitochondrial activities were evaluated with respiration, ATP synthesis and spectrophotometric assays. Mitochondrial mass was assessed by the fluorescent probe MitoTracker Red. RESULTS: In both cell types, all the treatments induced a severe defect of adipogenesis (low lipid content and decreased markers of adipogenic maturation: peroxisome proliferator-activated receptor [PPAR]gamma2 and aP2 but also uncoupling protein 1 in brown adipocytes) as well as altered mitochondrial function (decreased respiration rate and increased mitochondrial mass). Drug combination did not give additional toxicity. Brown adipocytes appeared more affected than white adipocytes (lower respiration rate and decreased ATP production). The mechanisms of mitochondrial toxicity differed with the drug and the cell type. Only stavudine induced severe mitochondrial DNA depletion in both cell types. With all the treatments, white adipocytes showed a decrease in the expression of mitochondrial and nuclear-DNA-encoded respiratory chain subunits (cytochrome c oxidase [CytOx]2 and CytOx4), whereas brown adipocytes maintained normal expression in accordance with their increase of the transcriptional factors of mitochondrial biogenesis nuclear respiratory factor 1 and PPARgamma coactivator (PGC)1-related cofactor PRC, but not PGC1alpha. CONCLUSION: Our results provide evidence for dissociation between mitochondrial activity, transcription and mitochondrial DNA content, highlighting the complexity of mitochondrial toxicity, which affects multiple cellular targets.
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https://www.hal.inserm.fr/inserm-00148353
Contributor : Marc Lombes <>
Submitted on : Monday, October 15, 2007 - 11:57:54 AM
Last modification on : Wednesday, September 16, 2020 - 4:54:13 PM
Long-term archiving on: : Thursday, April 8, 2010 - 5:24:06 PM

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  • HAL Id : inserm-00148353, version 1
  • PUBMED : 17926646

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Say Viengchareun, Martine Caron, Martine Auclair, Min-Ji Kim, Paule Frachon, et al.. Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes.: Adipocyte mitochondrial toxicity of antiHIV drugs. Antiviral Therapy, International Medical Press, 2007, 12 (6), pp.919-29. ⟨inserm-00148353⟩

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