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@ARTICLE{Vetralla:284337,
author = {Vetralla, Massimo and Wischhof, Lena and Kahsay, Asrat and
Cadenelli, Vanessa and Scifo, Enzo and Xie, Beijia and
Sbrissa, Miriana and Habert, Maelle and Ehninger, Dan and
Rizzuto, Rosario and Bano, Daniele and De Stefani, Diego},
title = {{TMEM}65-dependent {C}a2+ extrusion safeguards
mitochondrial homeostasis.},
journal = {Nature Communications},
volume = {17},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2026-00112},
pages = {923},
year = {2025},
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 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.},
keywords = {Animals / Mitochondria: metabolism / Caenorhabditis
elegans: metabolism / Caenorhabditis elegans: genetics /
Calcium: metabolism / Homeostasis / Caenorhabditis elegans
Proteins: metabolism / Caenorhabditis elegans Proteins:
genetics / Membrane Proteins: metabolism / Membrane
Proteins: genetics / Calcium Channels: metabolism / Calcium
Channels: genetics / Clonazepam: analogs $\&$ derivatives /
Clonazepam: pharmacology / Sodium-Calcium Exchanger:
metabolism / Sodium-Calcium Exchanger: genetics / Humans /
Mitochondrial Proteins: metabolism / Mitochondrial Proteins:
genetics / Thiazepines / Calcium (NLM Chemicals) /
Caenorhabditis elegans Proteins (NLM Chemicals) / Membrane
Proteins (NLM Chemicals) / Calcium Channels (NLM Chemicals)
/ Clonazepam (NLM Chemicals) / mitochondrial calcium
uniporter (NLM Chemicals) / Sodium-Calcium Exchanger (NLM
Chemicals) / CGP 37157 (NLM Chemicals) / Mitochondrial
Proteins (NLM Chemicals) / Thiazepines (NLM Chemicals)},
cin = {AG Bano / AG Ehninger},
ddc = {500},
cid = {I:(DE-2719)1013003 / I:(DE-2719)1013005},
pnm = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
(POF4-352)},
pid = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41408045},
pmc = {pmc:PMC12830682},
doi = {10.1038/s41467-025-67647-y},
url = {https://pub.dzne.de/record/284337},
}