Mst1 deletion reduces septic cardiomyopathy via activating Parkin‐related mitophagy

Abstract

Cardiomyocyte function and viability are highly modulated by mammalian Ste20-like kinase 1 (Mst1)-Hippo pathway and mitochondria. Mitophagy, a kind of mitochondrial autophagy, is a protective program to attenuate mitochondrial damage.However, the relationship between Mst1 and mitophagy in septic cardiomyopathy has not been explored. In the present study, Mst1 knockout mice were used in a lipopolysaccharide (LPS)-induced septic cardiomyopathy model. Mitophagy activity was measured via immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay. Pathway blocker and small interfering RNA were used to perform the loss-of-function assay. The results demonstrated that Mst1 was rapidly increased in response to LPS stress. Knockout of Mst1 attenuated LPS-mediated inflammation damage, reduced cardiomyocyte death, and improved cardiac function. At the molecular levels, LPS treatment activated mitochondrial damage, such as mitochondrial respiratory dysfunction, mitochondrial potential reduction, mitochondrial ATP depletion, and caspase family activation. Interestingly, in response to mitochondrial damage, Mst1 deletion activated mitophagy which attenuated LPSmediated mitochondrial damage. However, inhibition of mitophagy via inhibiting parkin mitophagy abolished the protective influences of Mst1 deletion on mitochondrial homeostasis and cardiomyocyte viability. Overall, our results demonstrated that septic cardiomyopathy is linked to Mst1 upregulation which is followed by a drop in the protective mitophagy. K E Y W O R D S mitochondrial damage, mitophagy, Mst1, Parkin, septic cardiomyopathy

Aldehyde Dehydrogenase 2 Protects Against Lipopolysaccharide-Induced Myocardial Injury by Suppressing Mitophagy

“…In response to LPS-mediated mitochondrial damage, deletion of mammalian Ste20-like kinase 1 (Mst1) activates mitophagy to protect mitochondria. However, repressing Parkin-mediated mitophagy abolishes the positive influence of Mst1 deletion on mitochondrial protection and myocardial cell viability (Shang et al, 2020). Dexmedetomidine (DEX) alleviates LPSinduced apoptosis and the inflammatory response of macrophages via PINK1-mediated mitophagy (Wang et al, 2019).…”

Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease

“…While canonical PINK-Parkin-dependent mitophagy preserves mitochondrial and cardiac function in diabetic mice with high-fat diet-induced cardiomyopathy [173], defects in PINK-Parkin-dependent mitophagy leads to severe cardiac complications in animal models of Duchenne muscular dystrophy [172]. The expression of negative regulators of cardiomyocyte mitophagy, such as the mammalian Ste20-like kinase 1 (Mst1), has also been documented in an experimental model of septic cardiomyopathy [174]. Notably, Mst1 depletion attenuates lipopolysaccharide (LPS)-induced cardiomyocyte death and preserves cardiac function via promoting Parkin-dependent mitophagy [174].…”

“…The expression of negative regulators of cardiomyocyte mitophagy, such as the mammalian Ste20-like kinase 1 (Mst1), has also been documented in an experimental model of septic cardiomyopathy [174]. Notably, Mst1 depletion attenuates lipopolysaccharide (LPS)-induced cardiomyocyte death and preserves cardiac function via promoting Parkin-dependent mitophagy [174]. Moreover, a role for the adenine nucleotide translocator (ANT) complex in mitophagy regulation via interaction with TIM23 has been described [175].…”

Mitochondrial Quality Control in Cardiomyocytes: A Critical Role in the Progression of Cardiovascular Diseases

“…In addition, mitophagy in cardiomyocytes is regulated by mammalian Ste20-like kinase 1 (Mst1), which rapidly increases in cardiomyocytes upon LPS treatment or diabetic stress. Mst1 depletion attenuates LPSinduced cardiomyocyte death or diabetic cardiomyopathy and improves cardiac function via promoting Parkin-dependent mitophagy (Shang et al, 2019). Further evidence reveals that the inhibition of mitophagy by Mst1 is associated with SIRT3, whereas depletion of SIRT3 restores cardiac function when Mst1 is overexpressed in diabetic cardiomyopathy .…”

“…Evidence suggests that decreased PINK1/Parkindependent mitophagy is associated with development of dystrophic cardiomyopathy (Kang et al, 2018). Recently, it has been reported that PINK1/Parkin-dependent mitophagy is regulated by several factors (Sun et al, 2014;Tahrir et al, 2017;Yu et al, 2017;Li G. et al, 2018;Pickles et al, 2018;Thai et al, 2018;Xiong et al, 2018;Ren J. et al, 2019;Shang et al, 2019). PTEN FIGURE 3 | Overview of mitochondrial biogenesis, fission and fusion in cardiomyocytes.…”