PHARMACOLOGIC EFFECTS ON MITOCHONDRIAL FUNCTION

The vast majority of energy necessary for cellular function is produced in mitochondria. Free-radical production and apoptosis are other critical mitochondrial functions. The complex structure, electrochemical properties of the inner mitochondrial membrane (IMM), and genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) are some of the unique features that explain why the mitochondria are vulnerable to environmental injury. Because of similarity to bacterial translational machinery, mtDNA translation is likewise vulnerable to inhibition by some antibiotics. The mechanism of mtDNA replication, which is required for normal mitochondrial maintenance and duplication, is inhibited by a relatively new class of drugs used to treat AIDS. The electrochemical gradient maintained by the IMM is vulnerable to many drugs that are weak organic acids at physiological pH, resulting in excessive free-radical generation and uncoupling of oxidative phosphorylation. Many of these drugs can cause clinical injury in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. The spectrum of drug-induced mitochondrial dysfunction extends across many drug classes. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of mitochondrial drug toxicity and patient safety. (C) 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:189-199.