Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

“…Of the ten most common drugs associated with drug-induced liver fatality, mitochondrial dysfunction/disruption is a major component in at least five of them. Furthermore, mitochondrial dysfunction plays a key role in non-hepatic drug toxicities such as cardiomyopathy and rhabdomyolysis [10][11][12][13].…”

“…Nonetheless, numerous experimental studies have shown mitochondrial impairment caused by TZDs that remain on the market. Rosiglitazone (and to a lesser degree, pioglitazone [53]) has been shown to inhibit OXPHOS complex I [13]. Rosiglitazone, like troglitazone, rapidly reduced mitochondrial transmembrane potential [14].…”

“…Additionally, consideration of non-liver mitochondrial toxicities (i.e. rhabdomyolysis) should not be forgotten, especially when glitazones are co-administered with statins [13,57,58].…”

Molecular mechanisms of toxicity of simvastatin, widely used cholesterol-lowering drug. A review

“…Simvastatin impairs mitochondrial respiration and inhibits oxidative phosphorylation Complexes I and II+III in isolated rat liver mitochondria [68]. These data suggest that simvastatin alters mitochondrial function directly, without the need for entering the cell and inhibiting HMG-CoA reductase.…”

“…Human skeletal muscle fibers Mitochondrial membrane depolarization, increase in mitochondrial NADH [14] Human skeletal muscle; rat skeletal muscle; rat ventricular cardiomyocytes Inhibition of the complex I of respiratory chain, disbalance of Ca2+ homeostasis [67] Human T, B and myeloma tumor cells Mitochondrial membrane depolarization, release of the second mitochondrial activator of caspases [41] HL-60 human leukemic cells Mitochondrial membrane depolarization, reactive oxygen species generation, cytochrome c leakage [49] PC3 human prostate cancer cell line Decrease in respiration rate, mitochondrial membrane depolarization [45] Murine tubular cells Cytochrome c release from the mitochondria, activation of caspase 3 [50] L6 rat skeletal muscle cell line;mitochondria from L6 cells Mitochondrial membrane depolarization;decrease in respiratory rate and betaoxidation, cytochrome c release [52] HepG2 cells Decrease in mitochondrial CoQ levels, decrease in ATP synthesis [46] Isolated rat liver mitochondria Impairement of mitochondrial respiration, inhibition of oxidative phosphorylation [68] Isolated mouse liver mitochondria Higher susceptibility to develop membrane permeability transition [69] cytotoxicity and mitotoxicity can highlight abnormalities and therefore reduce potentially damaging effects, would help us to understand why only 0.1% and up to 10% of patients receiving simvastatin treatment for hypercholesterolemia were in danger of adverse attack and to prevent the neopathy.…”