Molecular Control of Mitochondrial Ca2+ Efflux in Neurons [Mar. 18, 2026] 

Mitochondrial Ca²⁺ efflux controls neuronal metabolism and long-term memory across species (Nature Metabolism, 2026)
Summary: Neuronal mitochondrial Ca²⁺ normally acts as a transient metabolic signal during activity, but whether its clearance influences long-term memory remains unclear. This study shows that Letm1, a mitochondrial H⁺/Ca²⁺ exchanger involved in Ca²⁺ efflux, prolongs metabolic activation when depleted, promotes long-term memory formation in flies and mice, and suggests relevance to memory decline in neurodegenerative disorders.

Highlighted technique: Pyruvate enters mitochondrial metabolism through the TCA cycle, so the authors measured pyruvate flux to test whether Letm1 depletion truly increases mitochondrial metabolism, not just ATP levels. They expressed Pyronic, a FRET-based pyruvate sensor, in rat hippocampal neurons, blocked mitochondrial metabolism with sodium azide, and used the rate of cytosolic pyruvate buildup as a readout of pyruvate flow into mitochondria.

TMEM65 functions as the mitochondrial Na⁺/Ca²⁺ exchanger (Nature Cell Biology, 2025)
Summary: Mitochondrial Na⁺/Ca²⁺ exchange (mito-NCX) is the main pathway for clearing mitochondrial Ca²⁺ in neurons, but its molecular identity has remained unresolved despite NCLX being widely viewed as the leading candidate. This study shows that TMEM65 is necessary and sufficient for mito-NCX, thereby strongly identifying TMEM65 as the exchanger itself and redefining the molecular basis of mitochondrial Ca²⁺ efflux relevant to neurodegeneration and dementia.

Highlighted technique: TThe authors evaluated mitochondrial NCX (mito-NCX) activity by treating HEK293 cells with altered TMEM65 expression with digitonin, which permeabilized the plasma membrane while preserving mitochondria, and then monitoring Na+-induced Ca²⁺ release into the external medium using Calcium Green-5N. They also isolated mitochondria from the cells and measured total mitochondrial Ca²⁺ by extracting Ca²⁺ with BAPTA under denaturing conditions in the presence of SDS.