Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (P.W., S.X., J.X., Y.X., H.Z., B.Z., R.T., W.W.), University of Washington, Seattle.
Department of Laboratory Medicine and Pathology (Y.L., H.Z., H.X., W.W.), University of Washington, Seattle.
Circulation. 2022 Apr 5;145(14):1067-1083. doi: 10.1161/CIRCULATIONAHA.121.055841. Epub 2022 Feb 15.
Calcium (Ca) is a key regulator of energy metabolism. Impaired Ca homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca uniporter (MCU) in chronic stress-induced pathological cardiac remodeling.
MCU knockout or transgenic mice were infused with isoproterenol (ISO; 10 mg/kg per day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nmol/L, 48 hours). Intracellular Ca handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro.
Chronic administration of the β-adrenergic receptor agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. It is interesting that ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout mice. Cardiomyocytes from knockout mice or overexpressing a dominant negative MCU exhibited defective intracellular Ca handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca/calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated CREB (cAMP-response element binding protein), which bound the promoter to enhance gene transcription.
The β-adrenergic receptor/CaMKIIδB/CREB pathway upregulates gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca homeostasis and cardiomyocyte viability.
钙（Ca）是能量代谢的关键调节剂。钙稳态失调会损害线粒体，导致心肌细胞死亡、病理性肥大和心力衰竭。本研究探讨了线粒体钙单向转运体（MCU）在慢性应激诱导的病理性心脏重构中的调节和作用。
用异丙肾上腺素（ISO；每天 10mg/kg，持续 4 周）对 MCU 敲除或转基因小鼠进行输注。通过超声心动图和组织学评估心脏肥大和重构。用 ISO（1nmol/L，48 小时）处理原代培养的啮齿动物成年心肌细胞。监测细胞内 Ca 处理和细胞死亡途径。体外使用腺病毒介导的基因操作。
β肾上腺素能受体激动剂 ISO 的慢性给药增加了心脏线粒体中 MCU 和 MCU 复合物的水平，增加了线粒体 Ca 浓度，无论是在体内还是在体外。ISO 还上调了 MCU，而不影响其在成年心肌细胞中的调节蛋白。有趣的是，在全局 MCU 敲除小鼠中，ISO 诱导的心脏肥大、纤维化、收缩功能障碍和心肌细胞死亡加剧。来自敲除小鼠或过表达显性负性 MCU 的心肌细胞表现出细胞内 Ca 处理和多种细胞死亡途径的激活缺陷。相反，心脏特异性过表达 MCU 维持细胞内 Ca 稳态和收缩性，抑制细胞死亡，并防止 ISO 诱导的心脏肥大。ISO 通过激活 Ca/钙调蛋白激酶 II δB（CaMKIIδB）并通过钙调神经磷酸酶介导的丝氨酸 332 去磷酸化促进其核易位来上调 MCU 表达。核 CaMKIIδB 磷酸化 CREB（cAMP 反应元件结合蛋白），后者结合启动子以增强 基因转录。
β肾上腺素能受体/CaMKIIδB/CREB 通路上调心脏中的 基因表达。MCU 的上调是一种代偿机制，通过维持 Ca 稳态和心肌细胞活力来对抗应激诱导的病理性心脏重构。
