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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 μM), zidovudine (1 μM) and indinavir (10 μM), alone or in combination. Adipocyte fat content was measured with Oil Red O 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]γ2 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 PPARγ coactivator (PGC)1-related cofactor PRC, but not PGC1α.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.

Mitochondrial Toxicity of Indinavir, Stavudine and Zidovudine Involves Multiple Cellular Targets in white and brown adipocytes