SLC8B1 encodes NCLX (mitochondrial Na+/Ca2+ exchanger), a mitochondrial inner membrane antiporter essential for calcium homeostasis. NCLX mediates the exchange of 3 sodium ions per 1 calcium ion, enabling calcium efflux from mitochondria 1. This calcium extrusion is critical for mitochondrial function and cell survival, particularly in cardiomyocytes 2. Recent structural studies reveal NCLX functions as an H+/Ca2+ exchanger rather than solely Na+/Ca2+ exchanger, expanding understanding of its transport mechanisms 3. Mechanistically, NCLX regulates insulin secretion in pancreatic beta-cells by controlling mitochondrial calcium efflux and cytoplasmic calcium responses 4. NCLX also regulates store-operated calcium entry (SOCE) through sodium-dependent calcium shuttling that modulates mitochondrial redox status 5. Additionally, NCLX participates in hypoxic responses by influencing reactive oxygen species production and HIF-α stabilization 6. Clinically, SLC8B1 dysfunction causes severe pathology: deletion in adult mouse hearts triggers sudden cardiac death with fulminant heart failure due to mitochondrial calcium overload and increased superoxide production 2. Conversely, NCLX overexpression protects against ischemia-induced cardiomyocyte necrosis. NCLX also safeguards calcium homeostasis during embryonic development; mutations disrupt oocyte-to-embryo transition 7. These findings suggest augmenting mitochondrial calcium efflux may be therapeutically viable for cardiac and metabolic diseases.