The Permeability Transition Pore Controls Cardiac Mitochondrial Maturation and Myocyte Differentiation

Although mature myocytes rely on mitochondria as the primary source of energy, the role of mitochondria in the developing heart is not well known. Here, we find that closure of the mitochondrial permeability transition pore (mPTP) drives maturation of mitochondrial structure and function and myocyte differentiation. Cardiomyocytes at embryonic day (E) 9.5, when compared to E13.5, displayed fragmented mitochondria with few cristae, a less-polarized mitochondrial membrane potential, higher reactive oxygen species (ROS) levels, and an open mPTP. Pharmacologic and genetic closing of the mPTP yielded maturation of mitochondrial structure and function, lowered ROS, and increased myocyte differentiation (measured by counting Z bands). Furthermore, myocyte differentiation was inhibited and enhanced with oxidant and antioxidant treatment, respectively, suggesting that redox-signaling pathways lie downstream of mitochondria to regulate cardiac myocyte differentiation. [Display omitted] ► Prior to differentiation, myocardial mitochondria have few cristae and poor function ► Later, mitochondrial permeability transition pore (mPTP) closure enhances mitochondrial maturation ► This developmental maturation of mitochondria drives cardiomyocyte differentiation ► mPTP dynamics regulate cardiomyocyte differentiation via redox signaling