TMEM65, a mitochondrial inner-membrane protein, is crucial for regulating mitochondrial calcium (mCa2+) efflux through enhancing sodium (Na+)-dependent mCa2+ efflux via interacting with NCLX, a critical mCa2+ efflux route in excitable tissues [2,4]. It also plays roles in multiple biological processes and disease-related pathways, such as the PI3K-Akt-mTOR pathway [1].

Knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle, impairs cardiac and neuromuscular function [2,4]. In mouse hearts, disruption of Tmem65 function leads to impaired intercalated disc structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy [3]. In gastric cancer cells, silencing of TMEM65 suppresses cell proliferation, migration, invasion, and tumor growth both in vitro and in vivo [1].

In conclusion, TMEM65 is essential for maintaining mitochondrial calcium homeostasis and normal cardiac function. Its dysregulation is associated with various diseases, including gastric cancer and cardiomyopathy. Studies using gene-knockout (KO) mouse models have been crucial in revealing these functions and associations, providing insights into potential therapeutic strategies for related diseases.