Mitochondrial translational inhibitors in the pharmacopeia

Abstract

The vast majority of energy necessary for cellular function is produced in the mitochondria by the phosphorylation of ADP to ATP. Other critical mitochondrial functions include apoptosis and free-radical production. Chemical agents, including those found in the modern pharmacopeia, may impair mitochondrial function by a number of mechanisms. The mitochondria are vulnerable to environmental injury because of their complex physical structure, electrochemical properties of the inner mitochondrial membrane (IMM), dual genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) and inherent properties of the translational and transcriptional machinery. Mitochondria have evolved from alpha-proteobacteria and the residual structural similarity to bacterial translational machinery has left the mtDNA genes vulnerable to inhibition by commonly used translation-targeted antibiotics. Many of these medications cause adverse effects in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of the spectrum of disease caused by inhibition of mitochondrial translation and improve the safe and effective use of antibiotics that inhibit bacterial and human mitochondrial translation. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.