Li Yao, Liu Fengzhou, Chen Dongbo, Tian Yiyuan, Liu Chao, Li Fei
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Aerospace Clinical Medical Center, School of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China; Department of Aviation Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Cell Signal. 2025 Jan;125:111524. doi: 10.1016/j.cellsig.2024.111524. Epub 2024 Nov 23.
High-altitude cardiac injury is a prevalent form of tissue damage resulting from hypobaric hypoxia (HH). MICU1 is a critical modulator of mitochondrial calcium uptake, with significant implications for the regulation of mitochondrial redox homeostasis. This study sought to examine the impact of MICU1 and elucidate the underlying mechanism in myocardial exposed to HH.
Loss-and gain-of-function approaches were used to investigate the role of MICU1 in cardiac response to HH. In vitro, the function of MICU1 in the primary neonatal rat cardiomyocytes under hypoxia was examined.
We observed that MICU1 was downregulated in hearts exposed to HH, contributing to myocardial apoptosis. In vitro experiments demonstrated that MICU1 knockdown exacerbated hypoxic cardiomyocyte injury, as evidenced by an increase in apoptotic cells and a decrease in mitochondrial membrane potential. Conversely, overexpression of MICU1 in mice significantly mitigated myocardial injury, leading to enhanced cardiac function and reduced myocardial hypertrophy and fibrosis in hypobaric hypoxic mice, consistent with the in vitro findings. Further investigations revealed that overexpression of MICU1 inhibited apoptosis by augmenting mitochondrial Ca uptake and subsequently enhancing the activity of tricarboxylic acid cycle (TCA) related enzymes. Lastly, our results suggest that hypoxia-induced downregulation of MICU1 is mediated by the reduction of MAZ expression in primary neonatal rat cardiomyocytes.
Our results suggest that MICU1 plays an important role in myocardial protection subjected to HH, suggesting that enhancing the expression or activity of MICU1 may be a potential pharmacological target to ameliorate myocardial injury at high altitude.
高原心脏损伤是低压缺氧（HH）导致的一种常见组织损伤形式。MICU1是线粒体钙摄取的关键调节因子，对线粒体氧化还原稳态的调节具有重要意义。本研究旨在探讨MICU1的影响，并阐明其在暴露于HH的心肌中的潜在机制。
采用功能缺失和功能获得方法研究MICU1在心脏对HH反应中的作用。在体外，检测了MICU1在缺氧条件下原代新生大鼠心肌细胞中的功能。
我们观察到暴露于HH的心脏中MICU1表达下调，导致心肌细胞凋亡。体外实验表明，MICU1敲低加剧了缺氧心肌细胞损伤，凋亡细胞增加和线粒体膜电位降低证明了这一点。相反，在小鼠中过表达MICU1显著减轻了心肌损伤，导致低压缺氧小鼠心脏功能增强，心肌肥大和纤维化减少，这与体外研究结果一致。进一步研究表明，MICU1过表达通过增加线粒体钙摄取并随后增强三羧酸循环（TCA）相关酶的活性来抑制细胞凋亡。最后，我们的结果表明，缺氧诱导的MICU1下调是由原代新生大鼠心肌细胞中MAZ表达降低介导的。
我们的结果表明，MICU1在HH所致心肌保护中起重要作用，提示增强MICU1的表达或活性可能是改善高原心肌损伤的潜在药理学靶点。
