Abstract
SMADs are essential transcriptional effectors of transforming growth factor-β (TGFβ)/TGFβ-related signaling that underlies embryonic development and adult homeostasis. A recent study by Fang et al. in Cell Research adds to this biological complexity by demonstrating an atypical cytoplasmic role for SMAD5 in modulating the bioenergetic homeostasis (i.e., glycolysis and mitochondrial respiration) of cells in response to fluctuations in intracellular pH that is independent of receptor signaling.