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




Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes.: Adipocyte mitochondrial toxicity of antiHIV drugs - Download this document for free, or read online. Document in PDF available to download.

* Corresponding author 1 Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique 2 Pathologie de l-Adipocyte et des Cellules Hepatiques 3 Physiopathologie et thérapie du muscle strié 4 CHU Pitié-Salpêtrière APHP 5 Service d-Endocrinologie et Maladies de la reproduction

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 PPARgamma2 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 CytOx2 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 PGC1-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.

Keywords : mitochondria mitochondrial DNA mitochondrial biogenesis brown fat adipocyte





Author: Say Viengchareun - Martine Caron - Martine Auclair - Min-Ji Kim - Paule Frachon - Jacqueline Capeau - Marc Lombès - Anne Lombès

Source: https://hal.archives-ouvertes.fr/



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