MCUB (mitochondrial calcium uniporter dominant-negative subunit beta) is a negative regulator of the mitochondrial calcium uniporter (MCU) complex that functions to limit mitochondrial calcium overload during cellular stress 1. MCUB acts as a dominant-negative regulator by incorporating into the MCU channel pore and reducing—rather than abolishing—calcium transport proportional to MCUB protein levels, creating a tunable mechanism for regulating mitochondrial calcium uptake 2. This inhibition occurs through displacement of MCU from the functional channel complex and decreased association of calcium sensors MICU1 and MICU2, thereby preventing channel gating 3. Mechanistically, MCUB incorporation into tetrameric channels occurs at approximately 2:2 MCU:MCUB stoichiometry and requires the N-terminal domain of MCUB for expression 2. MCUB plays critical roles in metabolic regulation: it is induced during fasting in muscle cells to restrict mitochondrial calcium uptake, promoting fatty acid oxidation and metabolic reprogramming 4. Beyond metabolism, MCUB regulates macrophage polarization during skeletal muscle regeneration and controls pigmentation through negative regulation of the MCU-NFAT2-keratin signaling axis 5. Dysregulation of MCUB has clinical significance in disease: elevated MCUB expression in muscle-invasive bladder cancer stabilizes PD-L1 through inhibition of PRKN-dependent mitophagy, promoting immune evasion 6. Loss of MCUB function increases overall mitochondrial calcium uptake, leading to reduced fatty acid oxidation and progressive obesity 4.