Type 2 Diabetes mellitus (T2DM) has become a major public health issue associated with a high risk of late-onset Alzheimer’s disease (LOAD). Mitochondrial dysfunction is one of the molecular events that occur in the LOAD pathophysiology. The present study was planned to investigate the molecular alterations induced by hyperglycemia in the mitochondria of diabetic mice and further explore the possible ameliorative role of the mitochondria-targeted small peptide, SS31 in diabetic mice. For this purpose, we used a polygenic mouse model of type 2 diabetes, TALLYHO/JngJ (TH), and nondiabetic, SWR/J mice strains. The diabetic status in TH mice was confirmed by carrying out at 8 weeks of age. The 24 weeks old experimental animals were segregated into three groups: Nondiabetic controls (SWR/J mice), diabetic (TH mice) and, SS31 treated diabetic TH mice. mRNA and protein expression levels of mitochondrial proteins were investigated in all the study groups in the liver tissues using qPCR and immunoblot analysis. Also, the mitochondrial functions including H2O2 production, ATP generation, and lipid peroxidation were assessed in all the groups. Mitochondrial dysfunction was observed in TH mice as evident by significantly elevated H2O2 production, lipid peroxidation, and reduced ATP production. The mRNA expression and Western blot analysis of mitochondrial dynamics (Drp1 and Fis1 – fission; Mfn1, Mfn2, and Opa1 -fusion), and biogenesis (PGC-1α, Nrf1, Nrf2, and TFAM) genes were significantly altered in diabetic TH mice. Furthermore, SS31 treatment helps in a significant reduction the mitochondrial abnormalities and restore mitochondrial functions in diabetic TH mice.
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