Mst1 promotes cardiac ischemia–reperfusion injury by inhibiting the ERK-CREB pathway and repressing FUNDC1-mediated mitophagy

Abstract

Cardiac ischemia-reperfusion (I/R) injury results mainly from mitochondrial dysfunction and cardiomyocyte death. Mitophagy sustains mitochondrial function and exerts a pro-survival effect on the reperfused heart tissue. Mammalian STE20-like kinase 1 (Mst1) regulates chronic cardiac metabolic damage and autophagic activity, but its role in acute cardiac I/R injury, especially its effect on mitophagy, is unknown. The aim of this study is to explore whether Mst1 is involved in reperfusion-mediated cardiomyocyte death via modulation of FUN14 domain containing 1 (FUNDC1)-related mitophagy. Our data indicated that Mst1 was markedly increased in reperfused hearts. However, genetic ablation of Mst1 in Mst1-knockout (Mst1-KO) mice significantly reduced the expansion of the cardiac infarction area, maintained myocardial function and abolished I/R-mediated cardiomyocyte death. At the molecular level, upregulation of Mst1 promoted ROS production, reduced mitochondrial membrane potential, facilitated the leakage of mitochondrial pro-apoptotic factors into the nucleus, and activated the caspase-9-related apoptotic pathway in reperfused cardiomyocytes. Mechanistically, Mst1 activation repressed FUNDC1 expression and consequently inhibited mitophagy. However, deletion of Mst1 was able to reverse FUNDC1 expression and thus re-activate protective mitophagy, effectively sustaining mitochondrial homeostasis and blocking mitochondrial apoptosis in reperfused cardiomyocytes. Finally, we demonstrated that Mst1 regulated FUNDC1 expression via the MAPK/ERK-CREB pathway. Inhibition of the MAPK/ERK-CREB pathway prevented FUNDC1 activation caused by Mst1 deletion. Altogether, our data confirm that Mst1 deficiency sends a pro-survival signal for the reperfused heart by reversing FUNDC1-related mitophagy and thus reducing cardiomyocyte mitochondrial apoptosis, which identifies Mst1 as a novel regulator for cardiac reperfusion injury via modulation of mitochondrial homeostasis.

CFTR improves myocardial ischemic/reperfusion injury through activating FUNDC1-mediated mitophagy and regulating ATP and mitochondrial functions

“…Zhang et al reported that FUNDC1-mediated mitochondria protected heart from I/R injury through maintaining the mitochondrial homeostasis (28). In a recent study, Yu et al found through inhibition of FUNDC1-mediated mitophagy, MST1 could facilitate the cardiac I/R injury (29). In the present study, we also observed obvious inhibition of mitophagy during the I/R or H/R process.…”

Dissecting Molecular Mechanisms Underlying H2O2-induced Apoptosis of Mouse Bone Marrow Mesenchymal Stem Cell: Role of Mst1 Inhibition.

“…Mst1 promoted cardiomyocyte apoptosis via suppressing autophagy below the physiological levels under oxidative stress [30]. Given its regulating role for apoptosis and autophagy, Mst1 may be a new therapeutic target for preventing cardiomyocyte death [10,23]. In this study, Mst1 inhibition attenuated autophagy suppression, whereas autophagy inhibition by 3-MA application blocked the protective effects of Mst1 inhibition.…”

Role of Mitophagy in Cardiovascular Disease

“…I/R injury potentially increases BNIP3 phosphorylation at S17, enhance the binding affinity of LC3, and elevate mitophagy. During I/R, phosphorylation at Y18 and S13 are increased, LC3 affinity decreased with a reduction in mitophagy [97][98][99].…”