Targeting Diabetic Cardiomyopathy: LncRNA Kcnq1ot1 Rescues Mitochondrial ATP Synthase Via Sponging of MiR-378a-5p.

Diabetes mellitus has been linked to an increase in mitochondrial microRNA-378a (miR-378a) content. Twenty-five-week-old miR-378a knockout Db/Db mice display preserved mt-ATP6 and ATP synthase protein content, ATP synthase activity, and preserved cardiac function, supporting the hypothesis that miR-378a inhibition may be a therapeutic option for maintaining ATP synthase functionality during diabetes mellitus. Evidence also suggests that long non-coding RNAs (lncRNAs), including lncRNA potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (Kcnq1ot1), participate in regulatory axes with microRNAs (miRs). Prediction analyses indicate that Kcnq1ot1 has the potential to bind miR-378a. This study aimed to ascertain whether Kcnq1ot1 interacts with miR-378a to impact ATP synthase functionality by preserving mt-ATP6 levels. While miR-378a was confirmed to be significantly higher in type 2 diabetes mellitus (T2DM) patient and twenty-five-week-old Db/Db mouse mitochondria (P < 0.05), mitochondrial mt-ATP6 and Kcnq1ot1 levels were significantly reduced when compared to controls (P < 0.05). Assessments following Kcnq1ot1 overexpression in HL-1 cardiomyocytes overexpressing miR-378a revealed Kcnq1ot1 binding significantly reduced miR-378a levels, as indicated by reduced luciferase activity following transfection (P < 0.05). Further, Kcnq1ot1 overexpression reduced miR-378a levels (P < 0.05), and rescued mt-ATP6 and ATP synthase protein content (P < 0.05). Together, these data suggest that Kcnq1ot1 and miR-378a may act as constituents in an axis that regulates mt-ATP6 content, and that manipulation of this axis may provide benefit to ATP synthase functionality in the heart during type 2 diabetic insult.