TY  - JOUR
AU  - Vetralla, Massimo
AU  - Wischhof, Lena
AU  - Kahsay, Asrat
AU  - Cadenelli, Vanessa
AU  - Scifo, Enzo
AU  - Xie, Beijia
AU  - Sbrissa, Miriana
AU  - Habert, Maelle
AU  - Ehninger, Dan
AU  - Rizzuto, Rosario
AU  - Bano, Daniele
AU  - De Stefani, Diego
TI  - TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
JO  - Nature Communications
VL  - 17
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2026-00112
SP  - 923
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Mitochondria: metabolism
KW  - Caenorhabditis elegans: metabolism
KW  - Caenorhabditis elegans: genetics
KW  - Calcium: metabolism
KW  - Homeostasis
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Caenorhabditis elegans Proteins: genetics
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Calcium Channels: metabolism
KW  - Calcium Channels: genetics
KW  - Clonazepam: analogs & derivatives
KW  - Clonazepam: pharmacology
KW  - Sodium-Calcium Exchanger: metabolism
KW  - Sodium-Calcium Exchanger: genetics
KW  - Humans
KW  - Mitochondrial Proteins: metabolism
KW  - Mitochondrial Proteins: genetics
KW  - Thiazepines
KW  - Calcium (NLM Chemicals)
KW  - Caenorhabditis elegans Proteins (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Calcium Channels (NLM Chemicals)
KW  - Clonazepam (NLM Chemicals)
KW  - mitochondrial calcium uniporter (NLM Chemicals)
KW  - Sodium-Calcium Exchanger (NLM Chemicals)
KW  - CGP 37157 (NLM Chemicals)
KW  - Mitochondrial Proteins (NLM Chemicals)
KW  - Thiazepines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41408045
C2  - pmc:PMC12830682
DO  - DOI:10.1038/s41467-025-67647-y
UR  - https://pub.dzne.de/record/284337
ER  -