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.

Keywords: Cardiomyocytes; Maturation; Metabolic regulation; Mitochondria; Stem cells.

Fig. 1

Metabolic sensors and mitochondria. Metabolic sensors detect changes in oxygen, nutrient, or hormone levels to induce or inhibit mitochondrial biogenesis or removal by mitophagy. Crosstalk between the AMP-activated kinase (AMPK), hypoxia-inducible factor (HIF), and mechanistic target of rapamycin (mTOR) signaling pathways can alter the balance of mitochondrial responses to nutrients or other metabolic signals

Fig. 2

Metabolic transitions during development. Metabolic transitions from the embryonic to fetal to postnatal states regulate mitochondrial morphology and function, cell cycle state, cardiomyocyte maturation, and metabolite production

Fig. 3

Mitochondrial dynamics. Mitochondria undergo dynamic processes of biogenesis, fusion, fission, and mitophagy. Balance of fission and fusion processes are needed to maintain normal mitochondrial function. An imbalance of fission/fusion leads mitochondrial dysfunction: excessive fission can lead to cell death and excessive fusion is often seen in senescence. Nutrient sensors AMPK and mTOR can regulate mitochondrial biogenesis and mitophagy

Fig. 4

Mitochondrial permeability transition pore and cardiomyocyte development. During early development, the mPTP is open and increased ROS signaling facilitates cardiomyocyte differentiation. During later development, metabolic transitions trigger closure of the mPTP, which facilitates cardiomyocyte maturation. This is accompanied by an increase in the mitochondrial membrane potential and reduction in ROS, which also facilitate cardiomyocyte maturation. Abnormal opening of the mPTP can be triggered by elevated ROS, calcium, or glucose and can be seen in diseased states and may prevent cardiomyocyte maturation

Fig. 5

Quiescence and senescence in cardiomyocytes. Cardiomyocytes are proliferative during the fetal state but exit the cell cycle shortly after birth to enter a quiescent state. Stimuli including excessive glucose, insulin, or reactive oxygen species can induce a pathological senescent state. Cell cycle arrest with p53 upregulation leads to quiescence with inhibition of mTOR signaling but senescence with activation of mTOR signaling. In vitro culture conditions using high glucose or high insulin may also induce a senescent state and inhibition of these processes and promotion of quiescence may be important to promote cardiomyocyte maturation

Fig. 6

Summary of time course of metabolic changes affecting mitochondria and cardiomyocyte maturation. Dynamic changes in levels of substrates (pink) (oxygen, lactate, glucose, insulin, fatty acids, T3, glucocorticoids) affect the metabolic sensor signaling pathways (blue) (hypoxia-inducible factors (HIFs), mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK)) during fetal and postnatal cardiomyocyte development. These metabolic sensors can regulate mitochondrial function and coordinate mitochondrial dynamics throughout development. PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; mPTP, mitochondrial permeability transition pore