What Is in the Field for Genetics and Epigenetics of Diabetic Neuropathy: The Role of MicroRNAs

Figure 1

MIR499A polymorphism and miR-499a expression in DPN: hypothesis for a pathogenetic role in DPN. Mitochondrial dynamics are a continuous process of fusion, fission, biogenesis, and mitophagy that in neurons contrasts hyperglycemia-driven oxidative stress and maintains cellular bioenergetics [64, 73]. Mitochondrial dysfunction derives from persistent increase in metabolic load and oxidative stress in neurons in diabetes and is considered a relevant mechanism in the pathogenesis of DPN [65, 73]. Both dysregulation of the fission/fusion balance with increased fission and impaired biogenesis with reduced number of mtDNA have been found in diabetes. Recent studies have shown in people with type 2 diabetes (1) an association of the polymorphism rs3746444 of MIR499A with CAN and DPN [71], (2) a reduction in mtDNA copy number, more pronounced in the presence of DPN [72], (3) an association between this change in mtDNA copy number and the same polymorphism of MIR499A [72], (4) a reduced expression of miR-499a in subjects with DPN [46], and (5) in rat and human cardiomyocytes that miR-499a targets the gene of calcineurin (CnA), inhibits its expression and the CnA-mediated activation of dynamin-related protein (Drp) 1 responsible for mitochondrial fission and apoptosis [59, 60]. These findings allow the hypothesis that MIR499A polymorphism and changes in expression and function of miR-499a might affect both mitochondrial biogenesis and increase mitochondrial fission thus altering mitochondrial dynamics and leading to mitochondrial dysfunction and to DPN. It is not documented (dashed lines) that the studied MIR499A polymorphism affects miR-499 expression, and that in DPN, the reduced miR-499a expression is related to decreased mtDNA copy number and increased mitochondrial fission.