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082 _ _ |a 500
100 1 _ |a Vetralla, Massimo
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245 _ _ |a TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
260 _ _ |a [London]
|c 2025
|b Springer Nature
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520 _ _ |a 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.
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650 _ 7 |a Calcium
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650 _ 7 |a Caenorhabditis elegans Proteins
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650 _ 7 |a Membrane Proteins
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650 _ 7 |a Calcium Channels
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650 _ 7 |a Clonazepam
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650 _ 7 |a mitochondrial calcium uniporter
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650 _ 7 |a Sodium-Calcium Exchanger
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650 _ 7 |a CGP 37157
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650 _ 7 |a Mitochondrial Proteins
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650 _ 7 |a Thiazepines
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: metabolism
|2 MeSH
650 _ 2 |a Caenorhabditis elegans: genetics
|2 MeSH
650 _ 2 |a Calcium: metabolism
|2 MeSH
650 _ 2 |a Homeostasis
|2 MeSH
650 _ 2 |a Caenorhabditis elegans Proteins: metabolism
|2 MeSH
650 _ 2 |a Caenorhabditis elegans Proteins: genetics
|2 MeSH
650 _ 2 |a Membrane Proteins: metabolism
|2 MeSH
650 _ 2 |a Membrane Proteins: genetics
|2 MeSH
650 _ 2 |a Calcium Channels: metabolism
|2 MeSH
650 _ 2 |a Calcium Channels: genetics
|2 MeSH
650 _ 2 |a Clonazepam: analogs & derivatives
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650 _ 2 |a Clonazepam: pharmacology
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650 _ 2 |a Sodium-Calcium Exchanger: metabolism
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650 _ 2 |a Sodium-Calcium Exchanger: genetics
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650 _ 2 |a Humans
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650 _ 2 |a Mitochondrial Proteins: metabolism
|2 MeSH
650 _ 2 |a Mitochondrial Proteins: genetics
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650 _ 2 |a Thiazepines
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700 1 _ |a Wischhof, Lena
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700 1 _ |a Kahsay, Asrat
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700 1 _ |a Cadenelli, Vanessa
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700 1 _ |a Scifo, Enzo
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700 1 _ |a Xie, Beijia
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700 1 _ |a Sbrissa, Miriana
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700 1 _ |a Habert, Maelle
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700 1 _ |a Ehninger, Dan
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700 1 _ |a Rizzuto, Rosario
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700 1 _ |a Bano, Daniele
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700 1 _ |a De Stefani, Diego
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773 _ _ |a 10.1038/s41467-025-67647-y
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