A recent study has identified TMEM65, an inner mitochondrial membrane protein, as a key regulator of mitochondrial calcium homeostasis, a crucial mechanism for the metabolic health of tissues like the heart and brain. The research demonstrates that TMEM65 enhances the activity of NCLX, the mitochondrial sodium-calcium exchanger, which is vital for preventing calcium overload in excitable tissues.
Researchers utilized proximity-dependent biotinylation and proteomics to identify TMEM65 as a binding partner of NCLX. Experiments confirmed that TMEM65 actively boosts NCLX-mediated calcium extrusion, underscoring its functional significance in calcium dynamics. Loss-of-function studies further validated TMEM65's essential role in NCLX-dependent calcium efflux, as silencing TMEM65 expression led to increased mitochondrial calcium levels and subsequent cellular dysfunction.
Studies in mice revealed that Tmem65 knockdown resulted in mitochondrial calcium overload in heart and skeletal muscle cells, leading to impaired cardiac contractility and neuromuscular performance. These findings highlight the importance of TMEM65 in maintaining mitochondrial calcium balance and suggest that targeting TMEM65 function could restore this balance, potentially mitigating tissue damage in diseases characterized by mitochondrial calcium dysregulation. This discovery may have implications for treating neurodegenerative diseases, ischemic injury, and metabolic syndromes. Enhancing TMEM65 expression or function could protect against calcium-induced mitochondrial toxicity.