ROS-mitochondrial nexus in stem cell growth and differentiation and implications in cancer and degenerative diseases

Regenerative cells, also known as stem cells, exhibit transitioning between a resting state, crucial for long-term preservation with low metabolic activity, and an activation state defined by active proliferation and differentiation to repair old or damaged cells. Concomitant with stem cell transition, mitochondria also undergo a similar transition to support cell growth by providing energy and growth precursors. High mitochondrial activity during cell growth, however, results in reactive oxygen species (ROS). ROS function as signaling molecules and activate several metabolic pathways by rewiring key enzymes and proteins. During the resting state, often called quiescence, ROS production should be limited to prevent resumption of inappropriate growth and oxidation of essential components like DNA in a cell type whose main function is to divide and pass its genetic material to daughter cells for repair. Most stem cells in a resting state (also known as G0 phase) display reduced mitochondrial activity by suppressing oxidative phosphorylation (OXPHOS) due to active mitophagy maintained by quiescence regulators in cells. Mitogens and injury markers activate resting or quiescent stem cells to reenter the cell cycle and grow, a process that requires mitochondrial activity for the supply of nucleotides, non-essential amino acids, lipids and many more. Mitochondria undergo cell cycle-specific changes during the G1, S, and G2/M phases. This article examines how mitochondria regulate stem cell growth and control cell fate. Stem cell dysfunction leads to regeneration issues, contributing to premature aging and cancer. Understanding mitochondrial function can further enhance therapeutic interventions in cancer and aging, as highlighted at the end of the review.