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

Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA- deficient (p degrees) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. 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 p degrees and control cells containing mtDNA. Accordingly, experimentally increasing Delta psi m was sufficient to restore timely cell cycle progression in p degrees cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in p degrees cells with a recovered Delta psi m is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of Delta psi m as a regulator of cell cycle progression may have implications for disease states involving mitochondria l dysfunction.