Mst1 regulates post-infarction cardiac injury through the JNK-Drp1-mitochondrial fission pathway

Abstract

BackgroundPost-infarction cardiac injury is closely associated with cardiac remodeling and heart dysfunction. Mammalian STE20-like kinase 1 (Mst1), a regulator of cellular apoptosis, is involved in cardiac remodeling in post-infarction heart, but the mechanisms remain poorly defined. We aimed to explore the role of Mst1 in regulating chronic post-infarction cardiac injury, with a focus on mitochondrial homoeostasis.MethodsWild-type (WT) and Mst1-knockout mice were as the cardiac myocardial infarction model. Cardiac fibrosis, myocardial inflammation response, heart dysfunction and cardiomyocyte death were measured in vivo using immunohistochemistry, immunofluorescence, western blot, qPCR and TUNEL assays. Cardiomyocytes were isolated from WT and Mst1-knockout mice, and a chronic hypoxia model was used to induce damage. Mitochondrial function was determined via JC1 staining, ROS measurement, cyt-c leakage detection and mitochondrial apoptotic pathways analysis. Mitochondrial fission was observed using immunofluorescence. A pathway activator and inhibitor were applied to establish the signaling pathways involved in regulating mitochondrial homeostasis.ResultsOur study demonstrated that Mst1 expression was significantly upregulated in the heart post-infarction. Activated Mst1 induced cardiac fibrosis, an excessive inflammatory response, and cardiomyocyte death, whereas the genetic ablation of Mst1 protected the myocardium against chronic post-infarction injury. Function assays showed that upregulation of Mst1 activity contributed to JNK pathway activation, which led to Drp1 migration from the cytoplasm onto the surface of the mitochondria, indicative of mitochondrial fission activation. Excessive mitochondrial fission caused mitochondrial fragmentation, resulting in mitochondrial potential collapse, ROS overproduction, mitochondrial pro-apoptotic leakage into the cytoplasm, and the initiation of caspase-9-mediated mitochondrial apoptosis. By contrast, Mst1 deletion helped to maintain mitochondrial structure and function, sending pro-survival signals to the cardiomyocytes.ConclusionsOur results identify Mst1 as a malefactor in the development of post-infarction cardiac injury and that it acts through the JNK-Drp1-mitochondrial fission pathway.

Exendin‐4 protects the hearts of rats from ischaemia/reperfusion injury by boosting antioxidant levels and inhibition of JNK/p66Shc/NADPH axis

“…At the histological and ultrastructural levels, the LVs of I/R hearts showed severe cardiomyocytes and mitochondria damage, thus confirming the important role of the mitochondria in I/R‐induced cardiomyocyte oxidative stress and apoptosis. All these data are supported by many other studies of different animal models with different I/R protocols 43‐45 …”

Overexpression of Mst1 reduces gastric cancer cell viability by repressing the AMPK-Sirt3 pathway and activating mitochondrial fission

“…Similarly, in a model of mouse diabetes, the AMPK pathway promotes the survival of tubular epithelium by correcting excessive mitochondrial fission. 51 With respect to the MAPK-JNK pathway, in-depth studies have uncovered the cross-talk between the MAPK-JNK axis and mitochondrial fission in models of liver cancer metastasis, post-infarction cardiac injury, 52 endometriosis, rectal cancer, 12 and microvascular ischemia–reperfusion insult. 21 In the present study, we found that Mst1 overexpression inactivated the AMPK-Sirt3 pathway, which was accompanied by an increase in mitochondrial fission.…”

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

“…Finally, we found that mitochondrial fragmentation could be repressed by MKP1 via inhibiting the JNK-CaMKII-Fis1 pathway. Actually, previous experiments have identified a causal relationship between JNK activation and excessive mitochondrial fission [18,61]. In addition, CaMKII phosphorylation has been proved to be the early event regulating the balance between mitochondrial fission and fusion [62].…”