The Effect of S-15176 Difumarate Salt on Ultrastructure and Functions of Liver Mitochondria of C57BL/6 Mice with Streptozotocin/High-Fat Diet-Induced Type 2 Diabetes

SIMPLE SUMMARY: Type II diabetes mellitus (T2DM) is one of the most common diseases, which currently represents a major medical and social problem due to the chronic course, high rates of disability and mortality among patients. Mitochondria of the liver and other vital organs are one of the main targets of T2DM at the intracellular level. The pathological changes in the structure of mitochondria, hyperproduction of reactive oxygen species by the organelles, disorders in mitochondrial transport systems and ATP synthesis are now widely recognized as important factors in the development of diabetes. Therefore, treatment strategies to attenuate mitochondrial injury may result in cellular reprogramming and alleviation of the diabetes-related pathological complications. The aim of present work was to investigate the possible protective effect of S-15176, a potent derivative of the anti-ischemic agent trimetazidine, against mitochondrial damage in the liver of mice with experimental T2DM. The data indicate that S-15176 attenuates mitochondrial dysfunction and ultrastructural abnormalities in the liver of T2DM mice. The mechanisms underlying the protective effect of S-15176 are related to the stimulation of mitochondrial biogenesis and the inhibition of lipid peroxidation in the organelles. One may assume that the compound acts as a mitochondria-targeted metabolic reprogramming agent in T2DM. ABSTRACT: S-15176, a potent derivative of the anti-ischemic agent trimetazidine, was reported to have multiple effects on the metabolism of mitochondria. In the present work, the effect of S-15176 (1.5 mg/kg/day i.p.) on the ultrastructure and functions of liver mitochondria of C57BL/6 mice with type 2 diabetes mellitus (T2DM) induced by a high-fat diet combined with a low-dose streptozotocin injection was examined. An electron microscopy study showed that T2DM induced mitochondrial swelling and a reduction in the number of liver mitochondria. The number of mtDNA copies in the liver in T2DM decreased. The expression of Drp1 slightly increased, and that of Mfn2 and Opa1 somewhat decreased. The treatment of diabetic animals with S-15176 prevented the mitochondrial swelling, normalized the average mitochondrial size, and significantly decreased the content of the key marker of lipid peroxidation malondialdehyde in liver mitochondria. In S-15176-treated T2DM mice, a two-fold increase in the expression of the PGC-1α and a slight decrease in Drp 1 expression in the liver were observed. The respiratory control ratio, the level of mtDNA, and the number of liver mitochondria of S-15176-treated diabetic mice tended to restore. S-15176 did not affect the decrease in expression of Parkin and Opa1 in the liver of diabetic animals, but slightly suppressed the expression of these proteins in the control. The modulatory effect of S-15176 on dysfunction of liver mitochondria in T2DM can be related to the stimulation of mitochondrial biogenesis and the inhibition of lipid peroxidation in the organelles.