MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca²⁺ uniporter...

MICU1 is a calcium (Ca²⁺)-binding protein that regulates the mitochondrial Ca²⁺ uniporter channel complex (mtCU) and mitochondrial Ca²⁺ uptake. MICU1 knockout mice display disorganized mitochondrial architecture, a phenotype that is distinct from that of mice with deficiencies in other mtCU subunits and, thus, is likely not explained by changes in mitochondrial matrix Ca²⁺ content. Using proteomic and cellular imaging techniques, we found that MICU1 localized to the mitochondrial contact site and cristae organizing system (MICOS) and directly interacted with the MICOS components MIC60 and CHCHD2 independently of the mtCU. We demonstrated that MICU1 was essential for MICOS complex formation and that MICU1 ablation resulted in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, and cell death signaling. Together, our results suggest that MICU1 is an intermembrane space Ca²⁺ sensor that modulates mitochondrial membrane dynamics independently of matrix Ca²⁺ uptake. This system enables distinct Ca²⁺ signaling in the mitochondrial matrix and at the intermembrane space to modulate cellular energetics and cell death in a concerted manner.