Mitochondrial Ca 2+ homeostasis depends on coordinated uptake by the mitochondrial Ca 2+ uniporter complex and efflux via the Na + /Ca 2+ exchanger (mito-NCX) and the H + /Ca 2+ exchanger. These processes are critical for regulating mitochondrial metabolism, intracellular Ca 2+ signaling, and cell survival. This talk will begin with a brief overview of our work on the uniporter over the past decade, followed by recent findings on Ca 2+ efflux transporters. Using biochemical and functional assays, we show that TMEM65 is the mito-NCX, contrary to the longstanding belief that NCLX fulfills this role. TMEM65 forms a homodimer with essential ion-coordinating residues at the dimer interface and contains a binding site for the classical mito-NCX inhibitor CGP-37157. In parallel, we demonstrate that NCLX functions instead as a H + /Ca 2+ exchanger. Together, these findings provide a revised mechanistic framework for mitochondrial Ca 2+ handling and open new avenues for targeting Ca 2+ -driven pathologies.
Ming-Feng Tsai (Sun,) studied this question.