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

ABSTRACT: MicroRNA (miRNA) 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-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 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 downregulation of Mfn2 and cytosolic Ca²⁺ overload by weakening the buffering capability of mitochondria.

SUBMITTER: Qiu Y

PROVIDER: S-EPMC7036712 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Qiu Yue Y Cheng Rongchao R Liang Chaoqi C Yao Yuan Y Zhang Wenhao W Zhang Jie J Zhang Mingyu M Li Baiyan B Xu Chaoqian C Zhang Rong R

Molecular therapy. Nucleic acids 20200123

MicroRNA (miRNA) 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-the-art techniques. The results demonstrated that Mfn ...[more]

PMID: 32160705

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Project description:RationaleCaMKII (Ca2+-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca2+ handling and CaMKII activation in hypertrophy and HF.ObjectiveTo measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice.Methods and resultsWe used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions.ConclusionsWe conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKIIδC axis contributes to eccentric hypertrophy and HF.

Project description:Mitochondrial Ca2+ handling is accomplished by balancing Ca2+ uptake, primarily via the Ru360-sensitive mitochondrial calcium uniporter (MCU), Ca2+ buffering in the matrix and Ca2+ efflux mainly via Ca2+ ion exchangers, such as the Na+/Ca2+ exchanger (NCLX) and the Ca2+/H+ exchanger (CHE). The mechanism of CHE in cardiac mitochondria is not well-understood and its contribution to matrix Ca2+ regulation is thought to be negligible, despite higher expression of the putative CHE protein, LETM1, compared to hepatic mitochondria. In this study, Ca2+ efflux via the CHE was investigated in isolated rat cardiac mitochondria and permeabilized H9c2 cells. Mitochondria were exposed to (a) increasing matrix Ca2+ load via repetitive application of a finite CaCl2 bolus to the external medium and (b) change in the pH gradient across the inner mitochondrial membrane (IMM). Ca2+ efflux at different matrix Ca2+ loads was revealed by inhibiting Ca2+ uptake or reuptake with Ru360 after increasing number of CaCl2 boluses. In Na+-free experimental buffer and with Ca2+ uptake inhibited, the rate of Ca2+ efflux and steady-state free matrix Ca2+ [mCa2+]ss increased as the number of administered CaCl2 boluses increased. ADP and cyclosporine A (CsA), which are known to increase Ca2+ buffering while maintaining a constant [mCa2+]ss, decreased the rate of Ca2+ efflux via the CHE, with a significantly greater decrease in the presence of ADP. ADP also increased Ca2+ buffering rate and decreased [mCa2+]ss. A change in the pH of the external medium to a more acidic value from 7.15 to 6.8∼6.9 caused a twofold increase in the Ca2+ efflux rate, while an alkaline change in pH from 7.15 to 7.4∼7.5 did not change the Ca2+ efflux rate. In addition, CHE activation was associated with membrane depolarization. Targeted transient knockdown of LETM1 in permeabilized H9c2 cells modulated Ca2+ efflux. The results indicate that Ca2+ efflux via the CHE in cardiac mitochondria is modulated by acidic buffer pH and by total matrix Ca2+. A mechanism is proposed whereby activation of CHE is sensitive to changes in both the matrix Ca2+ buffering system and the matrix free Ca2+ concentration.

Dataset Information

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

Publications

MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca<sup>2+</sup> Cross-Talk.

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