MICU1 alleviates hypobaric hypoxia-induced myocardial injury through regulating Ca2+ uptake to inhibit mitochondria-dependent apoptosis

Abstract

Aim

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.

Methods

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.

Results

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 Ca²⁺ 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.

Conclusion

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.