MICU3 functions as a tissue-specific calcium sensor that regulates the mitochondrial calcium uniporter (MCU) channel, particularly in the central nervous system and skeletal muscle 1. MICU3 has higher calcium affinity compared to MICU1 and MICU2, allowing it to sense calcium levels via its EF-hand domains and lower the calcium threshold necessary for mitochondrial calcium permeation 1. Mechanistically, MICU3 forms a disulfide-linked heterodimer with MICU1 that undergoes conformational changes in response to calcium binding, moving away from the MCU pore to allow calcium uptake at higher calcium concentrations 2. In neurons, MICU3 enables axonal mitochondria to respond to small changes in external calcium, facilitating activity-driven ATP production and metabolic flexibility essential for neurotransmission 1. In skeletal muscle, MICU3 maintains mitochondrial calcium homeostasis and prevents age-related muscle dysfunction by reducing oxidative stress and apoptosis 3. Clinically, MICU3 expression is decreased in failing human hearts and during skeletal muscle aging 43. Its overexpression can induce cardiac hypertrophy, while its deficiency impairs presynaptic function and accelerates muscle aging, making MICU3 a potential therapeutic target for cardiovascular and neuromuscular disorders 43.