Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition in cardiac myocytes.

• DOI: 10.1096/fasebj.31.1_supplement.1080.6
• Publication Date: 2023-11-26T17:16:59Z
• Authors: Joseph Gordon; Wajihah Mughal; Jared Field; Yan Hai; Donald Chapman; Richard Keijzer; Sunil Rattan; Ian Dixon; Jianhe Huang; Michael Parmacek
• Keywords: Myocardin; Uniporter

Myocardin is a transcriptional co‐activator required for cardiovascular development and cardiomyocyte differentiation. Recent studies have shown that genetic inhibition of myocardin results in embryonic lethality with impaired proliferation increased programmed cell death. Mitochondrial permeability transition, triggered by matrix calcium accumulation, has been implicated regulated necrotic death, while transition pore closure involved myocyte differentiation mitochondrial maturation during development. We show loss function leads to endocardial necrosis, determined HMGB1 staining, at day 9.5, concurrent elevated expression the death gene Nix. Mechanistically, we demonstrate knockdown primary ventricular myocytes reduces microRNA‐133a levels allow Nix leading reduced respiration, necrosis. Using organelle‐targeted biosensors, sarcoplasmic reticulum (SR) release was prevented pharmacological inositol triphosphate (IP3)‐activated channel or uniporter. Gain confirm can desensitize elicited protein kinase‐A (PKA) activating agents opposing SR release. Furthermore, restoring mimicking oligonucleotides, rescues accumulation induced knockdown. Molecular using constructs targeted mitochondria revealed only SR‐targeted which could be attenuated Bcl‐2, but not mitochondrial‐targeted Bcl‐2. Finally, observed vivo within infarction border zone following coronary ligation rodents, corresponding expression. These findings identify novel myocardin‐regulated pathway maintains homeostasis development, ischemic heart disease. Support Funding Information Supported NSERC Canada, Thorlakson Foundation, Research Manitoba, Children's Hospital Foundation Manitoba.