Mitochondrial redox potential couples to single-cell mass in a conserved sublinear scaling law, modulated by mitochondrial mass-control genes

Using quantitative phase microscopy and reporter genes, we simultaneously measure single-cell dry mass and mitochondrial glutathione redox potential (steady-state mtROS) across eukaryotic cell types. We discover that mtROS scales inversely with single-cell mass according to a conserved sublinear power law, with cell-type-specific exponents spanning y = 0.1-0.5 across yeast, mouse, and human cells. Pharmacological and genetic perturbations of mtROS shift both the coefficient k and exponent y predictably while preserving the inverse relationship, indicating functional coupling of biomass accrual to mitochondrial redox state. A yeast knockout screen identifies 81 single-cell mass-control genes (scMCGs), enriched for mitochondrial metabolism and cristae maintenance. Conserved scMCGs, including human TRIAP1, ATPAF1, and ACO1, maintain the log-normal distribution of cell mass and stabilize the sublinear scaling exponent, likely by dampening noisy mtROS fluctuations that would otherwise perturb growth. These findings reveal a shared bioenergetic principle at the single-cell level, defining the allowable metabolic state space of eukaryotic cells. Mitochondrial OxPhos efficiency and redox byproducts are coupled to biomass accrual, and a conserved gene network tightly maintains this sublinear relationship. This scaling law provides a quantitative framework for understanding cell-size control, metabolic adaptation, and disease-associated growth dysregulation.