When do mitochondrial processes become instructive during pluripotent-state transitions

Abstract Pluripotent-state transitions are accompanied by coordinated changes in mitochondrial architecture, signaling, metabolism, and turnover, yet whether these changes drive, follow, or reciprocally interact with cell-state transitions remains incompletely resolved. Here, we evaluate evidence across three mitochondrial routes: architecture and positioning, mitochondria-to-nucleus communication, and mitochondrial quality control. Direct perturbation and rescue studies show that selected mitochondrial processes can promote or restrain pluripotency acquisition and transitions between pluripotent states. However, their effects depend on transition identity and phase, perturbation timing, duration and magnitude, species, and culture context. We therefore propose that mitochondrial processes should be considered instructive only when they bias a defined pluripotent-state transition through a state-relevant mechanism rather than simply altering cellular fitness or state stability.