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

Abstract

Background Cardiomyocytes that differentiate from pluripotent stem cells ( PSC s) 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 (m PTP ) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSC s. Methods and Results We induced cardiomyocyte differentiation from mouse and human PSC s and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from m PTP inhibition rather than from calcineurin inhibition. The m PTP inhibitor NIM 811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK 506 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 m PTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSC s.