MICU1 controls spatial membrane potential gradients and guides Ca²⁺ fluxes within mitochondrial substructures

Mitochondrial ultrastructure represents a pinnacle of form and function, with the inner mitochondrial membrane (IMM) forming isolated pockets of cristae membrane (CM), separated from the inner-boundary membrane (IBM) by cristae junctions (CJ). Applying structured illumination and electron microscopy, a novel and fundamental function of MICU1 in mediating Ca²⁺ control over spatial membrane potential gradients (SMPGs) between CM and IMS was identified. We unveiled alterations of SMPGs by transient CJ openings when Ca²⁺ binds to MICU1 resulting in spatial cristae depolarization. This Ca²⁺/MICU1-mediated plasticity of the CJ further provides the mechanistic bedrock of the biphasic mitochondrial Ca²⁺ uptake kinetics via the mitochondrial Ca²⁺ uniporter (MCU) during intracellular Ca²⁺ release: Initially, high Ca²⁺ opens CJ via Ca²⁺/MICU1 and allows instant Ca²⁺ uptake across the CM through constantly active MCU. Second, MCU disseminates into the IBM, thus establishing Ca²⁺ uptake across the IBM that circumvents the CM. Under the condition of MICU1 methylation by PRMT1 in aging or cancer, UCP2 that binds to methylated MICU1 destabilizes CJ, disrupts SMPGs, and facilitates fast Ca²⁺ uptake via the CM.