Effect of stavudine on mitochondrial genome and fatty acid oxidation in lean and obese mice

Like other antihuman immunodeficiency virus dideoxynucleosides, stavudine m ay occasionally induce lactic acidosis and perhaps lipodystrophy in metabol ically or genetically susceptible patients. We studied the effects of stavu dine on mitochondrial DNA (mtDNA), fatty acid oxidation, and blood metaboli tes in lean and genetically obese (ob/ob) mice. In lean mice, mtDNA was dep leted in liver and skeletal muscle, but not heart and brain, after 6 weeks of stavudine treatment (500 mg/kg/day). With 100 mg/kg/day, mtDNA transient ly decreased in liver, but was unchanged at 6 weeks in all organs, includin g white adipose tissue (WAT). Despite unchanged mtDNA levels, lack of signi ficant oxidative mtDNA lesions (as assessed by long polymerase chain reacti on experiments), and normal blood lactate/pyruvate ratios, lean mice treate d with stavudine for 6 weeks had increased fasting blood ketone bodies, due to both increased hepatic fatty acid beta -oxidation and decreased periphe ral ketolysis. In obese mice, basal WAT mtDNA was low and was further decre ased by stavudine. In conclusion, stavudine can decrease hepatic and muscle mtDNA in lean mice and can also cause ketoacidosis during fasting without altering mtDNA. Stavudine depletes WAT mtDNA only in obese mice. Fasting an d ketoacidosis could trigger decompensation in patients with incipient lact ic acidosis, whereas WAT mtDNA depletion could cause lipodystrophy in genet ically susceptible patients.