MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca2+ Cross-talk

Abstract MicroRNA and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca2+ handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca2+ cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-art techniques. The results demonstrated that Mfn2 was down-regulated and miR-20b was up-regulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by rAAV9-anti-miR-20b or 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 microRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca2+ into mitochondria, manifested as enhanced histamine-mediated Ca2+ release from mitochondrial, suggesting that Ca2+ reuptake/buffering capability of mitochondria to cytosolic Ca2+ is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca2+ overload and cardiac hypertrophy through Ca2+ signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through down-regulation of Mfn2 and cytosolic Ca2+ overload by weakening the buffering capability of mitochondria.