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.
Cohen
Bruce H
BH
Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA. cohenb2@ccf.org
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000900:Anti-Bacterial Agents / Q000633:toxicity; D019380:Anti-HIV Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005609:Free Radicals / Q000378:metabolism; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics; D051336:Mitochondrial Membranes / Q000187:drug effects; D055553:Prescription Drugs / Q000633:toxicity; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics
D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D005609:Free Radicals; D015386:Hazardous Substances; D055553:Prescription Drugs; D000255:Adenosine Triphosphate; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human