TY - JOUR
T1 - Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition
AU - Mughal, Wajihah
AU - Martens, Matthew
AU - Field, Jared
AU - Chapman, Donald
AU - Huang, Jianhe
AU - Rattan, Sunil
AU - Hai, Yan
AU - Cheung, Kyle G.
AU - Kereliuk, Stephanie
AU - West, Adrian R.
AU - Cole, Laura K.
AU - Hatch, Grant M.
AU - Diehl-Jones, William
AU - Keijzer, Richard
AU - Dolinsky, Vernon W.
AU - Dixon, Ian M.
AU - Parmacek, Michael S.
AU - Gordon, Joseph W.
N1 - Funding Information:
Acknowledgements This work was support by the Natural Science and Engineering Research Council (NSERC) Canada, through a Discovery Grant to JWG. Seed funding was provided by the Thorlakson Foundation Fund and the Children’s Hospital Foundation of Manitoba. MSP is support by NIH R01-HL102968 and R01-HL094520. I.M.D., V.W.D., and G.M.H. are supported by the Heart and Stroke Foundation of Canada. R.K. is a Thorlakson Chair in Surgical Research, and G.M.H. is a Canada Research Chair in Molecular Cardiolipin Metabolism. V.W.D. is the Ken Hughes Young Investigator and the Allen Rouse Fellow of the Manitoba Medical Services Foundation. J.W.G., V.W.D., G.M.H., and R.K. are members of the DEVOTION Research Cluster. W.M. is supported by a scholarship from the Children’s Hospital Foundation of Manitoba and Research Manitoba, J.F. is supported by a studentship from NSERC Canada, and L.K.C. is supported by a CIHR Fellowship. We thank Fuqin Zhu for assistance with the confocal microscopy.
Publisher Copyright:
© 2018, ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042873485&partnerID=8YFLogxK
U2 - 10.1038/s41418-018-0073-z
DO - 10.1038/s41418-018-0073-z
M3 - Journal Article
C2 - 29511336
AN - SCOPUS:85042873485
SN - 1350-9047
VL - 25
SP - 1732
EP - 1748
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 10
ER -