Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition

Cell Death Differ. 2018 Nov;25(10):1732-1748. doi: 10.1038/s41418-018-0073-z. Epub 2018 Mar 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cells, Cultured
  • Doxorubicin / pharmacology
  • Gene Expression / drug effects
  • Heart / drug effects
  • Isoproterenol / pharmacology
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Mitochondria / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Permeability / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Sarcoplasmic Reticulum / metabolism
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • BNIP3L protein, rat
  • MIRN133 microRNA, rat
  • Membrane Proteins
  • MicroRNAs
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Trans-Activators
  • myocardin
  • Doxorubicin
  • Isoproterenol
  • Calcium

Grant support