TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.

ABSTRACT: The bidirectional transport of Ca²⁺ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca²⁺ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na⁺/Ca²⁺ exchanger. Its downregulation chronically elevates basal [Ca²⁺]_mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65

SUBMITTER: Vetralla M 

PROVIDER: S-EPMC12830682 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature