TMEM65 functions as the mitochondrial Na⁺/Ca²⁺ exchanger.

ABSTRACT: Mitochondria export Ca²⁺ via Na⁺/Ca²⁺ exchange machinery (mito-NCX) to regulate intracellular Ca²⁺ signalling and mitochondrial Ca²⁺ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na⁺/Ca²⁺ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-rec

SUBMITTER: Zhang JL 

PROVIDER: S-EPMC12768467 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature