Targeting Diabetic Cardiomyopathy: LncRNA Kcnq1ot1 Rescues Mitochondrial ATP Synthase via Sponging of MiR‐378a‐5p

• Published in: The FASEB journal Vol. 36; no. S1
• Main Authors: Durr, Andrya J., Hathaway, Quincy A., Kunovac, Amina, Taylor, Andrew D., Rizwan, Saira, Cook, Chris C., Hollander, John M.
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01-05-2022
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R3403

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.