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• W4387500340 abstract "Abstract The balance between mitochondrial calcium ( m Ca 2+ ) uptake and efflux regulates ATP production, but if perturbed causes energy starvation or m Ca 2+ overload and cell death. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of m Ca 2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic m Ca 2+ overload. However, the mechanisms that regulate NCLX activity remain largely unknown. We used proximity biotinylation proteomic screening to identify the NCLX interactome and define novel regulators of NCLX function. Here, we discover the mitochondrial inner membrane protein, TMEM65, as an NCLX-proximal protein that potently enhances sodium (Na + )-dependent m Ca 2+ efflux. Mechanistically, acute pharmacologic NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in m Ca 2+ efflux. Further, loss-of-function studies show that TMEM65 is required for Na + -dependent m Ca 2+ efflux. Co-fractionation and in silico structural modeling of TMEM65 and NCLX suggest these two proteins exist in a common macromolecular complex in which TMEM65 directly stimulates NCLX function. In line with these findings, knockdown of Tmem65 in mice promotes m Ca 2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. We further demonstrate that TMEM65 deletion causes excessive mitochondrial permeability transition, whereas TMEM65 overexpression protects against necrotic cell death during cellular Ca 2+ stress. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent m Ca 2+ efflux, causing pathogenic m Ca 2+ overload, cell death and organ-level dysfunction, and that gain of TMEM65 function mitigates these effects. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent m Ca 2+ efflux and suggest modulation of TMEM65 as a novel strategy for the therapeutic control of m Ca 2+ homeostasis." @default.
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• W4387500340 date "2023-10-09" @default.
• W4387500340 modified "2023-10-17" @default.
• W4387500340 title "TMEM65 regulates NCLX-dependent mitochondrial calcium efflux" @default.
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• W4387500340 doi "https://doi.org/10.1101/2023.10.06.561062" @default.
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