Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart.

Mitochondrial Ca²⁺ elevations enhance ATP production, but uptake must be balanced by efflux to avoid overload. Uptake is mediated by the mitochondrial Ca²⁺ uniporter channel complex (MCUC), and extrusion is controlled largely by the Na⁺/Ca²⁺ exchanger (NCLX), both driven electrogenically by the inner membrane potential (ΔΨ_m). MCUC forms hotspots at the cardiac mitochondria-junctional SR (jSR) association to locally receive Ca²⁺ signals; however, the distribution of NCLX is unknown. Our fractionation-based assays reveal that extensively jSR-associated mitochondrial segments contain a minor portion of NCLX and lack Na⁺-dependent Ca²⁺ extrusion. This pattern is retained upon in vivo NCLX overexpression, suggesting extensive targeting to non-jSR-associated submitochondrial domains and functional relevance. In cells with non-polarized MCUC distribution, upon NCLX overexpression the same given increase in matrix Ca²⁺ expends more ΔΨ_m. Thus, cardiac mitochondrial Ca²⁺ uptake and extrusion are reciprocally polarized, likely to optimize the energy efficiency of local calcium signaling in the beating heart.

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