Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling

Large tumor suppressor kinase 2 (Lats2) is a member of the Hippo pathway, a critical regulator of organ size. Since Lats2 activity may trigger mitochondrial dysfunction, a key pathogenic factor in acute myocardial infarction (AMI), this study sought to investigate whether Lats2 deletion confers cardioprotection in AMI. AMI was induced in cardiomyocyte-specific Lats2 knockout (Lats2Cko) and control (Lats2flox) mice. Twenty-eight days after AMI surgery, myocardial performance and mitochondrial homeostasis were impaired in Lats2flox mice. In contrast, Lats2Cko mice exhibited markedly preserved cardiac structure and contraction/relaxation activity, decreased fibrosis, reduced circulating cardiac injury biomarker levels, and enhanced cardiomyocyte viability. Consistent with these findings, siRNA-mediated Lats2 silencing sustained mitochondrial respiration and inhibited apoptosis in hypoxia-treated HL-1 cardiomyocytes. Notably, Lats2 deficiency inhibited AMI/hypoxia-related mitochondrial fission and inactivated STING/p65 signaling by preventing hypoxia-induced release of mtDNA into the cytosol. Accordingly, pharmacological reactivation of STING signaling abolished the cardioprotective effects of Lats2 ablation. Those data suggest that AMI-induced Lats2 upregulation is associated with impaired cardiomyocyte viability and function resulting from enhanced mitochondrial fission, mtDNA release, and STING/p65 pathway activation.

Automated summary

This study shows that deletion of Lats2 gene can protect against acute myocardial infarction (AMI) by reducing cardiac injury and preserving cardiac structure and function. This protective effect may be attributed to the inhibition of mitochondrial fission, release of mtDNA, and activation of the STING/p65 pathway.