Diabetes is a metabolic disorder associated with mitochondrial (mt) dysfunction and oxidative stress. The molecular mechanisms involved in diabetes-associated neurological complications remain elusive. This study aims to investigate the protective effect of metformin (MF) on regulatory networks and integrated stress responses in brain tissue of Streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice were treated with MF (20 mg/kg BW), and whole brain tissue was harvested for further analysis. Protein carbonylation was measured as a marker of neuronal oxidative stress. Protein expression of mt chaperones, maintenance proteins, and regulators of the unfolded protein response (UPR) were measured by Western blot. Transcript levels of antioxidant enzyme GSTA4; mt biogenesis markers, ER stress regulators, and miR-132 and miR-148a were analysed using qPCR. The results showed that MF efficiently reduced protein carbonylation and oxidation. Mt function was improved by MF-treatment through upregulation of chaperone proteins (HSP60, HSP70 and LonP1). MF elicits the UPR to attenuate ER stress through a miR-132 repression mechanism. Additionally, MF was found to elevate deacetylases- Sirt1, Sirt3; and mt biogenesis marker PGC-1α through miR-148a repression. This is the first study to demonstrate the epigenetic regulation of mt maintenance by MF in diabetic C57BL/6 mouse whole brain tissue. We thus conclude that MF, beyond its anti-hyperglycaemic role, mediates neuroprotection through epigenomic and integrated stress responses in diabetic mice.
Keywords: Diabetes; Metformin; Mitochondrial dysfunction; Neurodegeneration; Reactive oxygen species (ROS); Unfolded protein response (UPR).
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