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Published on: August 10, 2021
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TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
Massimo Vetralla1,2, Lena Wischhof3, Asrat Kahsay1
1Department of Biomedical Sciences, University of Padova, Padova, Italy.
Nature Communications
|December 17, 2025
Summary
TMEM65 is identified as a key protein in mitochondrial calcium (Ca²⁺) efflux, facilitating calcium extrusion via sodium and lithium exchange. Its dysfunction impacts cellular development and may play a role in degenerative diseases.
Area of Science:
- Mitochondrial biology
- Cellular signaling
- Ion transport
Background:
- Mitochondrial calcium (Ca²⁺) transport is crucial for cellular functions.
- Calcium influx is primarily mediated by the Mitochondrial Calcium Uniporter (MCU) complex.
- Mitochondrial calcium efflux mechanisms are diverse, involving Na⁺ or H⁺ exchangers.
Purpose of the Study:
- To investigate the role of TMEM65 in mitochondrial calcium efflux.
- To elucidate the specific ion dependencies and regulatory mechanisms of TMEM65-mediated calcium transport.
Main Methods:
- Overexpression and downregulation of TMEM65 in cellular models.
- Measurement of mitochondrial Ca²⁺ levels and efflux rates.
- Pharmacological inhibition using CGP-37157.
- Genetic analysis in Caenorhabditis elegans.
Main Results:
- TMEM65 overexpression enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion.
- This effect is independent of the NCLX exchanger and sensitive to CGP-37157.
- TMEM65 downregulation leads to elevated basal mitochondrial Ca²⁺ and impaired efflux.
- Loss of TMEM65 homologs in C. elegans causes developmental defects under thermal stress, which are mitigated by inhibiting MCU-1.
Conclusions:
- TMEM65 is a novel component of the mitochondrial calcium efflux machinery.
- TMEM65 plays a significant role in maintaining mitochondrial calcium homeostasis.
- TMEM65 may be a potential therapeutic target in diseases associated with mitochondrial calcium overload.
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