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Fuente Pérez, Sergio De La 2025-09-16T12:17:44Z 2025-09-16T12:17:44Z 2018 De La Fuente S, Lambert JP, Nichtova Z, Fernandez Sanz C, Elrod JW, Sheu SS, Csordás G. Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart. Cell Rep. 2018 Sep 18;24(12):3099-3107.e4. doi: 10.1016/j.celrep.2018.08.040. PMID: 30231993; PMCID: PMC6226263. https://uvadoc.uva.es/handle/10324/77794 10.1016/j.celrep.2018.08.040. 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 (ΔΨm). 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 ΔΨm. Thus, cardiac mitochondrial Ca2+ uptake and extrusion are reciprocally polarized, likely to optimize the energy efficiency of local calcium signaling in the beating heart. eng info:eu-repo/semantics/openAccess Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart info:eu-repo/semantics/article