Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression

Mitochondria are central to numerous anabolic and catabolic pathways whereby mitochondrial dysfunction has a profound impact on metabolism and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on mito-cellular crosstalk to communicate mitochondrial distress to the rest of the cell. Such mito-cellular signaling slows cell cycle progression in mitochondrial-DNA deficient ({rho}0) Saccharomyces cerevisiae cells, but the initial trigger and the pathway mediating the response has remained unknown. Here, we show that decreased mitochondrial membrane potential ({Delta}{Psi}m) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both {rho}0 and control cells. Accordingly, experimentally increasing {Delta}{Psi}m was sufficient to restore timely cell cycle progression in {rho}0 cells. Neither the RTG retrograde pathway nor central DNA damage checkpoint kinases were involved in mediating this form of mito-cellular communication. The identification of {Delta}{Psi}m as a novel regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.