RetroGREAT signaling: The lessons we learn from yeast

The mitochondrial retrograde signaling (RTG) pathway of communication from mitochondria to the nucleus was first studied in yeast Saccharomyces cerevisiae. It rewires cellular metabolism according to the mitochondrial state by reprogramming nuclear gene expression in response to mitochondrial triggers. The main players involved in retrograde signaling are the Rtg1 and Rtg3 transcription factors, and a set of positive and negative regulators, including the Rtg2, Mks1, Lst8, and Bmh1/2 proteins. Retrograde regulation is integrated with other processes, including stress response, osmoregulation, and nutrient sensing through functional crosstalk with cellular pathways such as high osmolarity glycerol or target of rapamycin signaling. In this review, we summarize metabolic changes observed upon retrograde stimulation and analyze the progress made to uncover the mechanisms underlying the integration of regulatory circuits. Comparisons of the evolutionary adaptations of the retrograde pathway that have occurred in the different yeast groups can help to fully understand the process.