Drug-induced increased mitochondrial biogenesis in a liver biopsy.
Oncocytic changes seen in hepatocytes in patients receiving highly active antiretroviral therapy (HAART) are a result of mitochondrial damage. This is the first report that provides the electron microscopy illustration of mitochondrial proliferation as a result of the HAART drug Stavudine (Zerit) hepatotoxicity. The drug's effect on mitochondrial DNA replication leads to depleted mitochondrial-encoded proteins and configurational defects of the mitochondrial inner membrane leading to reduced and abnormal cristae, which house the electron transport chain and elementary bodies. This results in a decrease in the NAD/NADH ratio and reduces oxidative phosphorylation. The shift in the NAD/NADH ratio decreases the rate of fatty acid beta oxidation and oxidation of pyruvate by the Krebs cycle. Decreased oxidation of pyruvate drives it into an alternative pathway to form lactate leading to lactic acidosis. This mitochondrial dysfunction results in a compensatory increase in mitochondrial biogenesis, which results in oncocytic changes of the hepatocytes.
Kamal
Mohammad A
MA
Department of Pathology, Long Beach VA Medical Center, Long Beach, CA 90822, USA. mkamal@pol.net
French
Samuel W
SW
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D001706:Biopsy; D002779:Cholestasis / Q000139:chemically induced / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D018119:Stavudine / Q000009:adverse effects*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D018119:Stavudine