Background: Mitochondrial metabolism and signaling are dependent on mitochondrial Ca2+ (Ca2+m) and fusion dynamics. Ca2+m uptake is mediated by the mitochondrial calcium uniporter complex (mtCU), consisting of the MCU-EMRE pore, and the MICU1 and MICU2 gatekeepers. MICU1 and MICU2 have been always considered as synergistic siblings that cooperate to keep the mtCU in a closed state at resting cytosolic [Ca2+] ([Ca2+]c) and to open it when [Ca2+]c rises. MICU1 loss studies have also reported mitochondrial network fragmentation, and cristae structure derangement.
Aim: The underlying mechanisms of MICU1 in mitochondrial dynamics and fragmentation and the potential involvement of MICU2 in the mitochondrial structure alterations remains elusive. For this, we studied the role of MICU1 and MICU2 in mitochondrial dynamics using several genetic models and patient-derived cells,
Results: We show that MICU1 supports mitochondrial fusion independent of the mtCU, while MICU2 exerts an opposite effect. Mechanistically, we demonstrate that monomeric MICU1, through its C-terminal, interacts with mitochondrial fusion machinery, promoting mitochondrial fusion. Furthermore, we show that fusion support by MICU1 is required for mitochondrial network adaptation to acute metabolic challenges.
Conclusions: Our results uncover opposing roles for MICU1 and MICU2 in vital aspects of mitochondrial dynamics and reveal that MICU2 controls the various roles of MICU1 through heterodimerization. This likely contributes to the distinct clinical phenotypes associated with MICU1 and MICU2 mutations.