000284337 001__ 284337 000284337 005__ 20260126134855.0 000284337 0247_ $$2doi$$a10.1038/s41467-025-67647-y 000284337 0247_ $$2pmid$$apmid:41408045 000284337 0247_ $$2pmc$$apmc:PMC12830682 000284337 037__ $$aDZNE-2026-00112 000284337 041__ $$aEnglish 000284337 082__ $$a500 000284337 1001_ $$aVetralla, Massimo$$b0 000284337 245__ $$aTMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis. 000284337 260__ $$a[London]$$bSpringer Nature$$c2025 000284337 3367_ $$2DRIVER$$aarticle 000284337 3367_ $$2DataCite$$aOutput Types/Journal article 000284337 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1769431581_1864 000284337 3367_ $$2BibTeX$$aARTICLE 000284337 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000284337 3367_ $$00$$2EndNote$$aJournal Article 000284337 520__ $$aThe bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways. 000284337 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x0 000284337 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x1 000284337 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 000284337 650_7 $$0SY7Q814VUP$$2NLM Chemicals$$aCalcium 000284337 650_7 $$2NLM Chemicals$$aCaenorhabditis elegans Proteins 000284337 650_7 $$2NLM Chemicals$$aMembrane Proteins 000284337 650_7 $$2NLM Chemicals$$aCalcium Channels 000284337 650_7 $$05PE9FDE8GB$$2NLM Chemicals$$aClonazepam 000284337 650_7 $$2NLM Chemicals$$amitochondrial calcium uniporter 000284337 650_7 $$2NLM Chemicals$$aSodium-Calcium Exchanger 000284337 650_7 $$075450-34-9$$2NLM Chemicals$$aCGP 37157 000284337 650_7 $$2NLM Chemicals$$aMitochondrial Proteins 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