MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca(2+) Cross-Talk

MicroRNA (miRNA) and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca(2+) handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca(2+) cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-the-art techniques. The results demonstrated that Mfn2 was downregulated and miR-20b was upregulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-20b or miR-20b antisense inhibitor (AMO-20b). The deleterious action of miR-20b on Mfn2 expression/function and mitochondrial ATP synthesis was observed and reversed by rAAV9-anti-miR-20b or AMO-20b. The targeted regulation of miR-20b on Mfn2 was confirmed by luciferase reporter and miRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca(2+) into mitochondria, manifested as enhanced histamine-mediated Ca(2+) release from mitochondrial, suggesting that Ca(2+) reuptake/buffering capability of mitochondria to cytosolic Ca(2+) is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca(2+) overload and cardiac hypertrophy through Ca(2+) signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through downregulation of Mfn2 and cytosolic Ca(2+) overload by weakening the buffering capability of mitochondria.