Background:  NRTI-mediated mitochondrial DNA (mtDNA) depletion has been hypothesized to result in mitochondrial toxicity with subsequent lipoatrophy. However, until now a correlation between mtDNA depletion and respiratory chain activity has never been performed in primary human subcutaneous preadipocytes and adipocytes.
Methods: We studied adipocyte phenotype, viability, mtDNA content, and activity of respiratory chain complexes (I+III, II+III, IV, and V) and citrate synthase in proliferating and differentiating primary human subcutaneous preadipocyte. Cells were exposed to zidovudine (AZT; 6 µM or 180 µM), stavudine (d4T; 3 µM or 90 µM), and zalcitabine (ddC; 0.1 µM or 3 µM) during proliferation and differentiation for as long as 40 days.
Results:  At therapeutic drug concentration, d4T and ddC induced an almost 40% depletion (control 100%±12.7%; d4T 53.5%±15.3%; ddC 59.5%±1.6%; p <0.05) in differentiating adipocytes. At higher drug concentrations both d4T- and ddC-treated cells demonstrated about 60% mtDNA depletion (control 100%±14.7%; d4T 44%±7.9%; ddC 42.6%±4.9%; p <0.05). Under this experimental conditions AZT did not lead to mtDNA depletion at any dose tested. In none of the treated cultures mtDNA depletion was associated with major changes in adipocyte phenotype or viability. Furthermore despite mtDNA depletion by NRTI at the end of differentiation process, activity of the respiratory chain complexes (I+III, II+III, IV, and V) and citrate synthase were found to be unimpaired. We obtained similar results in proliferating preadipocytes.
Conclusions:  NRTI-induced depletion of mtDNA in as much as 60% in differentiating human adipocytes was not associated with impaired respiratory chain activity in vitro.