The role of cyclophilin D in interspecies differences in susceptibility to hepatotoxic drug-induced mitochondrial injury

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Graphical abstractTest compound A ((5Z)-6-[(2R,3S)-3-({[(4-Chloro-2-methylphenyl)sulfonyl]amino}methyl) bicyclo[2.2.2]oct-2-yl]hex-5-enoic acid) was withdrawn from premarketing clinical trials due to severe liver injury. Intracellular accumulation of lipids (steatosis) has been observed in human-derived cells and may account for the severe hepatotoxicity. Mitochondrial β-oxidation and ketogenesis play a fundamental role in energy homeostasis. Mitochondrial dysfunction can therefore cause severe deficiency in fatty acid oxidation and apoptosis which finally triggers the hepatocellular injury. Some of hepatotoxic drugs (e.g., salicylic acid, diclofenac and troglitazone) are known to induce mitochondrial dysfunction. This study therefore examined the effect of compound A on the mitochondrial permeability transition (MPT) and membrane potential in mitochondria isolated from mouse, rat and monkey livers. The incubation of rat and monkey mitochondria energized by succinate in the presence of Ca2+ (20 μM) and compound A (2.5–10 μM) resulted in cyclosporin A (CsA)-sensitive MPT pore opening and a decline in mitochondrial membrane potential in a concentration-dependent manner. However, mouse mitochondria showed low susceptibility to compound A-induced dysfunction. Rat mitochondrial expression of cyclophilin D (CyPD) was about twice that of mouse mitochondria, but the expression levels of other MPT pore proteins (adenine nucleotide translocator and voltage-dependent anion channel) were comparable in both species. An assessment of the effect of compound A on CyPD knockdown cells demonstrated that mitochondrial susceptibility to compound A was attenuated in CyPD knockdown cells. These results suggest that an interspecies difference in the susceptibility to mitochondrial dysfunction induced by compound A exists as a result of species-specific discrepancies in CyPD expression.

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