Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Abstract

Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

Hypertrophic Cardiomyopathy in Infants from the Perspective of Cardiomyocyte Maturation

“…However, mitochondria are regarded as central mediators triggering maturation of cardiomyocytes during the metabolic transition in cardiomyocytes. 16) These findings suggest that normoxia, enteral feeding, and hormonal changes during the perinatal window affect mitochondria, and mitochondria can regulate cell cycle activity and electrophysiological properties of cardiomyocytes.…”

“…These factors have been comprehensively reviewed in articles underscoring the mitochondria as playing a central role in maturation of immature cardiomyocytes by producing sufficient ATP and sensing metabolic transitions, including oxygen and hormones. 16) …”

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

“…For example, some neuronal cell types may benefit from co-culture with glial cells to achieve functional maturity [ 181 , 182 ]. Cell maturity significantly impacts on mitochondrial content and morphology [ 160 , 183 ]. Therefore, it is important to consider the suitability of a differentiation and maturation technique for any desired endpoints.…”

“…It was proposed that the underlying defects in OXPHOS lead to an ATP deficit [ 149 , 159 ], which affects storage and handling of calcium by the sarcoplasmic reticulum and cardiomyocyte contractility [ 137 ]. Therefore, treatments targeting mitochondrial function or biogenesis could improve ATP production to support normal contractility in SCO2 mutant iPSC-CMs [ 3 , 160 ]. The benefits of bezafibrate treatment seen in the SURF1 hPSC models support this as a treatment option for SCO2 iPSC-CMs.…”

Fetal Gene Reactivation in Pulmonary Arterial Hypertension: GOOD, BAD, or BOTH?

“…The transition from proliferative to mature cardiomyocytes is driven by a changing energy substrate and utilization with fatty acid oxidation as the preferential source of energy [21]; a switch directly associated with mitochondrial reorganization (increased number and size). One of the major regulators of this metabolic shift include the hypoxia-inducible factor 1-alpha (HIF1α) [22]. Highly expressed and stabilized under low-oxygen conditions, as those experienced by the intrauterine environment, HIF1α promotes and enhances the glycolytic program by activating glycolytic genes such as glucose transporters, lactate dehydrogenase A (LDHA), hexokinase 2 (HK2) and pyruvate kinase muscle isozyme M2 (PKM2) and by modulating expression and activity of peroxisome proliferator-activated receptors (PPARs), PPAR gamma coactivator 1 (PGC1α), and heart and neural crest derivatives expressed 1 (HAND1), leading to repression of lipid oxidation [23,24].…”