%0 Journal Article
%A Vetralla, Massimo
%A Wischhof, Lena
%A Kahsay, Asrat
%A Cadenelli, Vanessa
%A Scifo, Enzo
%A Xie, Beijia
%A Sbrissa, Miriana
%A Habert, Maelle
%A Ehninger, Dan
%A Rizzuto, Rosario
%A Bano, Daniele
%A De Stefani, Diego
%T TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
%J Nature Communications
%V 17
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DZNE-2026-00112
%P 923
%D 2025
%X 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 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.
%K Animals
%K Mitochondria: metabolism
%K Caenorhabditis elegans: metabolism
%K Caenorhabditis elegans: genetics
%K Calcium: metabolism
%K Homeostasis
%K Caenorhabditis elegans Proteins: metabolism
%K Caenorhabditis elegans Proteins: genetics
%K Membrane Proteins: metabolism
%K Membrane Proteins: genetics
%K Calcium Channels: metabolism
%K Calcium Channels: genetics
%K Clonazepam: analogs & derivatives
%K Clonazepam: pharmacology
%K Sodium-Calcium Exchanger: metabolism
%K Sodium-Calcium Exchanger: genetics
%K Humans
%K Mitochondrial Proteins: metabolism
%K Mitochondrial Proteins: genetics
%K Thiazepines
%K Calcium (NLM Chemicals)
%K Caenorhabditis elegans Proteins (NLM Chemicals)
%K Membrane Proteins (NLM Chemicals)
%K Calcium Channels (NLM Chemicals)
%K Clonazepam (NLM Chemicals)
%K mitochondrial calcium uniporter (NLM Chemicals)
%K Sodium-Calcium Exchanger (NLM Chemicals)
%K CGP 37157 (NLM Chemicals)
%K Mitochondrial Proteins (NLM Chemicals)
%K Thiazepines (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41408045
%2 pmc:PMC12830682
%R 10.1038/s41467-025-67647-y
%U https://pub.dzne.de/record/284337