Phosphate Starvation Signaling Increases Mitochondrial Membrane Potential through Respiration-independent Mechanisms

The mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential mostly by inducing the expression of the electron transport chain but also activates the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited by either phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of the mitochondrial membrane potential is evolutionarily conserved as it also is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that the mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement even under conditions of mitochondrial dysfunction.