Chronic hyperglycemia impairs mitochondrial unfolded protein response and precipitates proteotoxicity in experimental diabetic neuropathy: focus on LonP1 mediated mitochondrial regulation

Background: Disturbed mitochondrial homeostasis has been identified to contribute to the pathogenesis of diabetic neuropathy (DN). However, the role of Mitochondrial Lon peptidase 1 (Lonp1) and Heat shock proteins (HSP's) in DN remains elusive. Here we studied the role of these proteins in experimental DN.

Methods: Rats were injected with STZ (55 mg/kg, ip) to induce diabetes. After confirmation of diabetes, animals were maintained for 8 weeks to develop neuropathy. Resveratrol was administered at two dose levels 10 and 20 mg/kg for last 2 weeks. Neuronal PC12 cells was challenged with 30 mM of β-D glucose to evaluate the molecular changes.

Results: Diabetic rats showed reduced expression of various mitochondrial proteases in dorsal root ganglions (DRG). This effect may increase proteotoxicity and diminish electron transport chain (ETC) activity as evident by increased protein oxidation and reduced ETC complexes activities under diabetic condition. In particular, we focused on our efforts to characterize the expression pattern of Lonp1 which was found to be significantly (p < 0.01 vs. control group) under expressed in DRG of diabetic rats. We used Resveratrol to characterize the importance of Lonp1 in regulation of mitochondrial function. High glucose (HG) (30 mM) exposed PC12 cells suggested that Resveratrol treatment attenuated the HG induced mitochondrial damage via induction of mitochondrial proteases. Moreover, siRNA directed against Lonp1 has impaired the activity of Resveratrol in attenuating the HG induced mitochondrial dysfunction.

Conclusion: These results would signify the importance of modulating mitochondrial proteases for the therapeutic management of DN.

Keywords: Diabetic neuropathy; Electron transport chain; Mitochondrial Lon protease; Proteostasis; Resveratrol; UPRmt.