Mitochondria and drugs

Mitochondria play a central role in the life and death of cells. They are not merely the centre for energy metabolism, but are also the headquarters for different catabolic and anabolic processes, calcium fluxes, and various signalling pathways. Mitochondria maintain homeostasis in the cell by interacting with reactive oxygen-nitrogen species and responding adequately to different stimuli. In this context, the interaction of pharmacological agents with mitochondria is an aspect of molecular biology that is too often disregarded, not only in terms of toxicology but also from a therapeutic point of view, especially considering the potential therapeutic applications related to the modulation of mitochondrial activity.At the mitochondrial level, there are several potential drug targets that can lead to toxicity, but only for few of them, a real clinical counterpart has been demonstrated. Recently, antiviral nucleoside analogues have shown mitochondrial toxicity through the inhibition of DNA polymerase-gamma. Other drugs targeted to different components of the mitochondrial channels can disrupt ion homeostasis or affect the mitochondrial permeability transition pore. Many molecules are known inhibitors of the mitochondrial electron transport chain, interfering with one or more of the complexes in the respiratory chain. Some drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), may lead to uncoupling of oxidative phosphorylation, while the mitochondrial toxicity of other drugs seems to depend on the production of free radicals, although this mechanism has yet to be defined. Besides toxicity, other drugs have been targeted to mitochondria to treat mitochondrial dysfunctions. Many drugs have been recently developed to target the mitochondria of cancer cells in order to trigger apoptosis or necrosis. The aim of this chapter is to underline the role of mitochondria in pharmacology and toxicology, stressing all the potential therapeutic approaches being due to iatrogenic modulation of the multitude of mitochondrial activities.