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Considering the complexity of mitochondria, it is not surprising that the pathogenesis of adverse drug events often develop on drug-induced mitochondrial injury. Drug induced mitochondrial toxicity can occur through several mechanisms, such as depletion of mtDNA (e.g. NRTI), inhibition of fatty acid beta-oxidation (e.g. valproic acid), opening of the mitochondrial permeability transition pore (e.g. anthracyclines), formation of mitochondrial oxidative stress and depletion of mitochondrial glutathione pool (e.g. acetaminophen), uncoupling of electron transport from ATP synthesis (e.g. tamoxifen) and inhibition of mitochondrial electron transport chain complexes (e.g. simvastatin). This review focuses on the mitochondrial toxicity of drugs in general and explains the practical relevance of these adverse drug events according to specific drugs (metformin, statins, acetaminophen, valproic acid). Furthermore the significance of mitotropic micronutrients such as coenzyme Q10, L-carnitine and glutathione in the prevention and management ofdrug-induced mitochondrial injury is discussed.

The injury of the visceral organs liver, stomach/intestine and pancreas by ischemia and reperfusion can be understood as a process, the events of which represent junctions in pathogenetic networks. In the phase of ischemia, damage of cells by oxygen deficiency is the center of the injurious process. The initial event is the decreased mitochondrial energy supply. Changes in ion homeostasis, activation of hydrolases as well as formation of large pores in the mitochondrial membranes, the so-called mitochondrial permeability transition, are other decisive events in the network of the hypoxic cell injury. Cell damage in the phase of reperfusion is either a consequence of changes in the cells, originating from the phase of ischemia, or the result of an inflammatory tissue reaction. In both cases reactive oxygen species are important triggers of the cell damage. Disturbances of the glutathione equilibrium and of the calcium balance as well as again the mitochondrial permeability transition and the activation of hydrolases belong to the events in the network of cell injury in this phase. Even more than the intracellular events of the cell damage, the events of the inflammatory tissue reaction are linked net-like with one another. Initiated by cells already damaged, an increased release of reactive oxygen species, nitrogen monoxide and other mediators, activation of macrophages, neutrophils, endothelial cells, lymphocytes and the complement system as well as disturbances of the microcirculation form a network of interacting events, which leads to a perpetuation of the tissue damage. A multiplicity of injurious pathways can be designed due to the net-like linkage of the events of the cell and tissue damage. An important consequence, which results from the construct of the pathogenetic networks, is therefore the demand that an effective therapy of the ischemia-reperfusion injury of visceral organs can be attained only by blockade of several central junctions.