Mass Control Genes Buffer a Conserved Sublinear Scaling Law Linking Single-Cell Dry Mass to Mitochondrial Redox Efficiency

Using quantitative phase microscopy and genetically-encoded metabolism probes, we simultaneously measured single-cell dry mass and mitochondrial redox efficiency across eukaryotic cell types. We discovered that single-cell mass scales with mitochondrial redox efficiency, according to a sublinear power law, across budding yeast, mouse, and human cells. Genetic and pharmacological perturbations of mitochondrial redox balance shifted the coefficient k and exponent y predictably, while preserving the scaling law, indicating a causative coupling between biomass accrual and mitochondrial redox efficiency. We also discovered that both single-cell mass and mitochondrial redox efficiency manifest log-normal distributions, providing more support for previous theories that biomass accrual is an exponential process, meaning the rate of mass increase depends on the current mass. Finally, our yeast knockout screen identified 81 mass control genes (MCGs) that disrupted the log-normality of single-cell mass. Interestingly, MCGs were enriched for mitochondrial metabolism and cristae maintenance, whereas <10% were related to the cell cycle. Conserved MCGs, including human TRIAP1, ATPAF1, and ACO1, also maintained human single-cell mass log-normality and sublinear scaling with mitochondrial redox efficiency. These findings reveal a shared bioenergetic principle at the single-cell level, and new techniques to study it. This scaling law provides a quantitative framework for understanding cell mass control, metabolic coupling, and disease-associated growth regulation.