Journal Article

DZNE-2026-00112

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.

Vetralla, M. ; Wischhof, L. (First author)DZNE* ; Kahsay, A. ; Cadenelli, V. ; Scifo, E.DZNE* ; Xie, B.DZNE* ; Sbrissa, M. ; Habert, M.DZNE* ; Ehninger, D.DZNE* ; Rizzuto, R. ; Bano, D.DZNE* ; De Stefani, D.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-67647-y

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.

Keyword(s): Animals (MeSH) ; Mitochondria: metabolism (MeSH) ; Caenorhabditis elegans: metabolism (MeSH) ; Caenorhabditis elegans: genetics (MeSH) ; Calcium: metabolism (MeSH) ; Homeostasis (MeSH) ; Caenorhabditis elegans Proteins: metabolism (MeSH) ; Caenorhabditis elegans Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Calcium Channels: metabolism (MeSH) ; Calcium Channels: genetics (MeSH) ; Clonazepam: analogs & derivatives (MeSH) ; Clonazepam: pharmacology (MeSH) ; Sodium-Calcium Exchanger: metabolism (MeSH) ; Sodium-Calcium Exchanger: genetics (MeSH) ; Humans (MeSH) ; Mitochondrial Proteins: metabolism (MeSH) ; Mitochondrial Proteins: genetics (MeSH) ; Thiazepines (MeSH) ; Calcium ; Caenorhabditis elegans Proteins ; Membrane Proteins ; Calcium Channels ; Clonazepam ; mitochondrial calcium uniporter ; Sodium-Calcium Exchanger ; CGP 37157 ; Mitochondrial Proteins ; Thiazepines

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Contributing Institute(s):

1. Aging and Neurodegeneration (AG Bano)
2. Translational Biogerontology (AG Ehninger)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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