Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition

Wajihah Mughal, Matthew Martens, Jared Field, Donald Chapman, Jianhe Huang, Sunil Rattan, Yan Hai, Kyle G. Cheung, Stephanie Kereliuk, Adrian R. West, Laura K. Cole, Grant M. Hatch, William Diehl-Jones, Richard Keijzer, Vernon W. Dolinsky, Ian M. Dixon, Michael S. Parmacek, Joseph W. Gordon

    Research output: Contribution to journalJournal Articlepeer-review

    33 Citations (Scopus)


    Myocardin is a transcriptional co-activator required for cardiovascular development, but also promotes cardiomyocyte survival through an unclear molecular mechanism. Mitochondrial permeability transition is implicated in necrosis, while pore closure is required for mitochondrial maturation during cardiac development. We show that loss of myocardin function leads to subendocardial necrosis at E9.5, concurrent with elevated expression of the death gene Nix. Mechanistically, we demonstrate that myocardin knockdown reduces microRNA-133a levels to allow Nix accumulation, leading to mitochondrial permeability transition, reduced mitochondrial respiration, and necrosis. Myocardin knockdown elicits calcium release from the endo/sarcoplasmic reticulum with mitochondrial calcium accumulation, while restoration of microRNA-133a function, or knockdown of Nix rescues calcium perturbations. We observed reduced myocardin and elevated Nix expression within the infarct border-zone following coronary ligation. These findings identify a myocardin-regulated pathway that maintains calcium homeostasis and mitochondrial function during development, and is attenuated during ischemic heart disease. Given the diverse role of Nix and microRNA-133a, these findings may have broader implications to metabolic disease and cancer.

    Original languageEnglish
    Pages (from-to)1732-1748
    Number of pages17
    JournalCell Death and Differentiation
    Issue number10
    Publication statusPublished - 1 Nov. 2018


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