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In this study, Ouyang et al. present important findings on the regulation of mitochondrial membrane potential (MMP) in yeast through Oxphos dependent and independent mechanisms. The authors propose that cells maintain an MMP set-point in response to environmental cues like phosphate starvation to preserve mitochondrial functions such as protein import. Elegant genetic screens identify that the deletion protein phosphatase Sit4 increases MMP through reversed activity of the ATP synthase. Interestingly, phosphate starvation of yeast cells is observed to elicit signaling via the cyclin dependent kinase PHO85. The resultant increase in MMP is dependent on ATP/ADP carrier and ATP hydrolysis by ATP synthase. The authors also extend their findings to Drosophila and mammalian cells, suggesting the existence of a conserved phosphate signaling response across eukaryotes. Thus, this study provides a better understanding of mechanisms regulating mitochondrial bioenergetics and can therefore have broader therapeutic applications.