Abstract
S-15176 difumarate salt, a derivative of the anti-ischemic metabolic drug trimetazidine, has been intensively studied for its impact on cellular metabolism in animal models of ischemia-reperfusion injury of the liver, heart, spinal cord, and other organs. Despite evidence of some reduction in oxidative damage to cells, the results of therapy with S-15176 have been mostly disappointing, possibly because of the lack of data on its underlying mechanisms. Here, we aimed to investigate in more detail the role of complexes I-IV of the electron transport chain and membrane permeability transition in mitochondrial toxicity associated with S-15176. Using rat thymocyte and liver mitochondria, we demonstrated that: (1) acute exposure to S-15176 (10 to 50 μM) dose-dependently decreased the mitochondrial membrane potential; (2) S-15176 suppressed the ADP-stimulated (State 3) and uncoupled (State 3UDNP) respiration of mitochondria energized with succinate or malate/glutamate, but not ascorbate/TMPD, and increased the resting respiration (State 4) when using all the substrate combinations; (3) S-15176 directly inhibited the activity of the respiratory complex III; (4) low doses of S-15176 diminished the rate of H2O2 production by mitochondria; (5) at concentrations of above 30 μM, S-15176 reduced calcium retention capacity and contributed to mitochondrial membrane permeabilization. Taken together, these findings suggest that S-15176 at tissue concentrations reached in animals can impair mitochondrial function through suppression of the cytochrome bc1 complex and an increase in the nonspecific membrane permeability.
Funder
Russian Science Foundation
Subject
General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology
Cited by
1 articles.
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