Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells

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Background-Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we show that inhibition of the mitochondrial permeability transition pore (mPTP) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSCs. Methods and Results-We induced cardiomyocyte differentiation from mouse and human PSCs and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from mPTP inhibition rather than from calcineurin inhibition. The mPTP inhibitor NIM811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK506 only slightly increased cardiomyocyte differentiation. CsA-treated cells showed an increase in mitochondrial calcium, mitochondrial membrane potential, oxygen consumption rate, ATP level, and expression of genes related to mitochondrial function. Furthermore, inhibition of mitochondrial oxidative metabolism reduced the cardiomyogenic effect of CsA while antioxidant treatment augmented the cardiomyogenic effect of CsA. Conclusions-Our data show that mPTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSCs.
Publisher
WILEY-BLACKWELL
Issue Date
2014-04
Language
English
Article Type
Article
Keywords

PHYSIOLOGICAL ROLES; ENERGY-METABOLISM; CARDIAC MYOCYTES; MOUSE; HEART; PROGENITORS; THERAPY; CARDIOMYOGENESIS; PURIFICATION; REGENERATION

Citation

JOURNAL OF THE AMERICAN HEART ASSOCIATION, v.3, no.2

ISSN
2047-9980
DOI
10.1161/JAHA.113.000693
URI
http://hdl.handle.net/10203/189308
Appears in Collection
MSE-Journal Papers(저널논문)BS-Journal Papers(저널논문)
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