Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate

Recent evidence supports the notion that mitochondrial metabolism is necessary for the determination of stem cell fate. Historically, mitochondrial metabolism is linked to the production of ATP and tricarboxylic acid (TCA) cycle metabolites to support stem cell survival and growth, respectively. However, it is now clear that beyond these canonical roles, mitochondria as signaling organelles dictate stem cell fate and function. In this review, we focus on key conceptual ideas on how mitochondria control mammalian stem cell fate and function through reactive oxygen species (ROS) generation, TCA cycle metabolite production, NAD⁺/NADH ratio regulation, pyruvate metabolism, and mitochondrial dynamics. There is a growing appreciation that beyond the canonical roles of producing ATP and biosynthetic intermediates, mitochondria as signaling organelles can dictate stem cell fate and function. Here, we discuss multiple mechanisms by which mitochondrial metabolism controls mammalian stem cell fate.