Connecting Mitochondria, Metabolism, and Stem Cell Fate

Abstract

As sites of cellular respiration and energy production, mitochondria play a central role in cell metabolism. Cell differentiation is associated with an increase in mitochondrial content and activity and with a metabolic shift toward increased oxidative phosphorylation activity. The opposite occurs during reprogramming of somatic cells into induced pluripotent stem cells. Studies have provided evidence of mitochondrial and metabolic changes during the differentiation of both embryonic and somatic (or adult) stem cells (SSCs), such as hematopoietic stem cells, mesenchymal stem cells, and tissue-specific progenitor cells. We thus propose to consider those mitochondrial and metabolic changes as hallmarks of differentiation processes. We review how mitochondrial biogenesis, dynamics, and function are directly involved in embryonic and SSC differentiation and how metabolic and sensing pathways connect mitochondria and metabolism with cell fate and pluripotency. Understanding the basis of the crosstalk between mitochondria and cell fate is of critical importance, given the promising application of stem cells in regenerative medicine. In addition to the development of novel strategies to improve the in vitro lineage-directed differentiation of stem cells, understanding the molecular basis of this interplay could lead to the identification of novel targets to improve the treatment of degenerative diseases.

FIG. 1.

Mitochondria and metabolism remodeling upon pluripotent stem cell differentiation and reprogramming. Pluripotent stem cells display globular immature mitochondria, localized perinuclearly, characterized by an electron-lucid matrix and poorly developed cristae. Energy production in pluripotent stem cells is mainly generated by a high glycolysis rate, leading to increased lactate production, whereas oxidative phosphorylation (OXPHOS) activity is limited, leading to reduced oxygen consumption and reactive oxygen species (ROS) production. Although substrate entry into the tricarboxylic acid (TCA) cycle is limited, intermediates of glycolysis enter the pentose phosphate pathway (PPP) and serve as substrates for the nucleotide synthesis required to sustain self-renewal. In differentiated cells, a more developed mitochondrial network, characterized by a more electron-dense matrix and developed cristae, ensures ATP production through increased OXPHOS activity. This results in elevated oxygen consumption and ROS production and reduced production of lactate through glycolysis. Interestingly, inhibiting OXPHOS or stimulating glycolysis impedes stem cell differentiation while favoring reprogramming into induced pluripotent stem cells (iPSCs). In contrast, stimulating mitochondrial biogenesis favors cell differentiation, whereas inhibiting glycolysis impairs reprogramming. Color images available online at www.liebertpub.com/scd

FIG. 2.

Pathways involved in the interplay between pluripotency, mitochondrial biogenesis, and metabolism. On the one hand, energy-, nutrient-, and environment-sensing pathways regulate both pluripotency and metabolism through their effects on glycolysis and mitochondrial biogenesis and activity. On the other hand, mitochondrial activity regulates stemness and differentiation through various mechanisms. These involve, for example, the production of ROS, which can induce or prevent the commitment to specific differentiation lineages; the production of intermediates or cofactors influencing epigenetic marks, protein activity, and stability; and the modification of the redox or energy status of the cells, thus altering nutrient- and energy-sensing pathways. AMPK, AMP-activated protein kinase; IF1, inhibitory factor I; LKB1, liver kinase B1; HIF-1α, hypoxia-inducible factor1α; mTORC1, mammalian target of rapamycin complex I; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; PHD, prolyl hydroxylase domain-containing protein; PKCλ/ι, protein kinase C isoform lambda/iota; TCA, tricarboxilic acid; TSC2, tuberous sclerosis complex 2; α-KG, α-ketoglutarate. Color images available online at www.liebertpub.com/scd