Current Concepts in Drug‐Induced Mitochondrial Toxicity

Abstract

Mitochondria generate most of the cell's ATP and play key roles in fatty acid oxidation, steroid synthesis, heme synthesis, thermogenesis, calcium homeostasis, and apoptosis. With the development of new methods to study mitochondrial function, it is becoming clear that drug-induced mitochondrial dysfunction is one of the causes of drug toxicity. Mitochondria can be impaired by drugs in a variety of ways. These include inhibition of oxidative phosphorylation, uncoupling of electron transport from ATP synthesis, irreversible opening of the mitochondrial permeability transition pore, inhibition of transporters within the mitochondrial inner membrane, increased oxidative stress, inhibition of the citric acid cycle, inhibition of fatty acid oxidation, and impairment of either mtDNA replication or mtDNA-encoded protein synthesis. This unit provides an overview on the physiological roles of mitochondria and the mechanisms by which they can be adversely affected by drugs.

Phenotypic Profiling of Raf Inhibitors and Mitochondrial Toxicity in 3D Tissue Using Biodynamic Imaging

“…23 There are many known mitochondrial toxins that work through different mechanisms. Valinomycin is a potassium ionophore that induces rapid dissipation of the mitochondrial membrane potential (MMP) without adversely affecting the viability.…”

Mitochondrial Dysfunction on the Toxic Effects of Anticancer Agents— From Lab Bench to Bedside

“…The IMS contains proteins such as the adenylate kinase and the creatine kinase (CK), as well as the cytochrome c and the apoptosis-inducing factor (AIF), which translocate to the cytoplasm during the apoptotic process, and other proteins involved in cellular metabolism. The proteins involved in the Krebs cycle, in the fatty acid oxidation, as well as in the synthesis of the heme and steroids, are located in the matrix [8,9,12,13]. The mitochondrial matrix also contains the mitochondrial DNA (mtDNA).…”

“…Thus, the oxidative phosphorylation is coupled to the ATP requirements and the electron flow along the electron transport chain only occurs when the synthesis of ATP is required. The IMM impermeability ensures that the proton pumping along the respiratory chain is coupled to ATP synthesis [8,12,14]. Structure of mitochondria and main mechanisms by which anticancer agents affect mitochondrial functions.…”

“…The heart, the kidneys, and the central nervous system, which have high energetic demands and are heavily dependent on oxidative phosphorylation, are more prone to the impact of mitochondrial damage. On the other hand, considering the exposure to high concentrations of drugs, the liver is another common organ showing mitochondrial dysfunction [12].…”

Cardiolipin profiles as a potential biomarker of mitochondrial health in diet‐induced obese mice subjected to exercise, diet‐restriction and ephedrine treatment

“…The physiologic importance of CL is underscored by the clinical signs in patients with BS; these include dilated cardiomyopathy, skeletal muscle weakness, growth delay, intermittent or chronic neutropenia, 3‐methylglutaconic aciduria, chronic fatigue, arrhythmias and sudden death. Furthermore, the major side effects of various drugs have been attributed to mitochondrial dysfunction/toxicity and subsequent withdrawal of promising drugs from the market (Nadanaciva and Will, ; Pereira et al ., ). As abhorrent CL content and composition have been implicated in other diseases of mitochondrial dysfunction, we aimed to evaluate CL as a potential marker in diet‐induced obesity.…”