Empowering self-renewal and differentiation: the role of mitochondria in stem cells

Abstract

Stem cells are characterized by their multi-lineage differentiation potential (pluripotency) and their ability for self-renewal, which permits them to proliferate while avoiding lineage commitment and senescence. Recent studies demonstrate that undifferentiated, pluripotent stem cells display lower levels of mitochondrial mass and oxidative phosphorylation, and instead preferentially use non-oxidative glycolysis as a major source of energy. Hypoxia is a potent suppressor of mitochondrial oxidation and appears to promote "stemness" in adult and embryonic stem cells. This has lead to an emerging paradigm, that mitochondrial oxidative metabolism is not just an indicator of the undifferentiated state of stem cells, but may also regulate the pluripotency and self-renewal of stem cells. The identification of specific mitochondrial pathways that regulate stem cell fate may therefore enable metabolic programming and reprogramming of stem cells.

Fig. 1

Stem cells increase mitochondrial oxidation upon differentiation. This schematic figure depicts an overview of the mitochondrial activity shift that occurs with differentiation of an undifferentiated pluripotent stem cells. The immature stem cell (top) is characterized by high nuclear levels of pluripotency regulators such Oct-4 and Nanog, lower mitochondrial mass and peri-nuclear mitochondria. In this undifferentiated state, cells rely on glycolysis for their energy needs and mitochondrial oxidation is suppressed, thus resulting in lower mitochondrial ATP production and ROS release. Upon differentiation (bottom), the pluripotency regulators decrease, while the mitochondrial mass, mitochondrial oxidation, and ROS production increase. Some studies suggest that mitochondrial ROS may act as signaling mediators that direct cell differentiation or self-renewal by shifting redox states. Additional mitochondrial signaling mediators and products such as calcium or ATP may also be important and the definitive roles of such mediators have not yet been established