TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.

ABSTRACT: The balance between mitochondrial calcium (_mCa²⁺) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of _mCa²⁺ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic _mCa²⁺ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na⁺)-dependent _mCa²⁺ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion

SUBMITTER: Garbincius JF 

PROVIDER: S-EPMC12087536 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature