Vitamin C is a physiological modulator for mitochondrial calcium uptake.

Mitochondrial calcium homeostasis is critical for bioenergetics, cell signaling, and cell survival and death, but its regulatory mechanism remains largely unknown. Here, a mitochondria-targeted genetically encoded calcium indicator has revealed that physiological concentrations of ascorbic acid (vitamin C) suppress mitochondrial calcium uptake in both intact living cells and permeabilized cells and enhance intracellular calcium signaling compared with ascorbate-deprived conditions. Mechanistic analyses indicate that this effect is mediated by a reduction in mitochondrial membrane potential, the primary driving force for mitochondrial calcium uptake. These findings uncover an unrecognized role of ascorbic acid in mitochondrial calcium homeostasis. Given the roles of mitochondrial calcium in neurodegeneration and cancer cell bioenergetics, our findings provide new insights into disease pathophysiology and potential therapeutic strategies.