Saturday, May 10, 2025
5/10/2025
Mitochondrial Calcium Uniporter in Signaling and Dynamics - Mitochondrial Ca2+ uptake controls many cell functions, including energy metabolism, signaling and dynamics. Mitochondrial Ca2+ accumulation is supported by the robust driving force of the highly negative, inner mitochondrial membrane potential, but is activated only during Ca2+ signals, when cytoplasmic [Ca2+] is elevated. Ca2+ signals are propagated to the mitochondrial matrix through a channel, the calcium uniporter (mtCU), comprised of pore-forming MCU, scaffold EMRE, and Ca2+-sensing regulatory dimers of MICU1 with itself, MICU2 or MICU3. MICU1 deletion results in a permanently open mtCU, whereas MICU2 loss increases and MICU3 loss decreases the Ca2+ sensitivity of the mtCU gating. MICU1 deletion has been shown by us and others to cause perinatal death in mouse and both MICU1 and MICU2 mutations have been linked to human diseases. Evidence has also started to accumulate in support of MICU1 decrease in common disorders like ischemia-reperfusion and cancer. However, despite the MICUs broad disease relevance, their contribution to the organization of calcium signaling and organelle, cell and tissue structure and functions remains undetermined. Here we present preliminary data indicating cell-to-cell and intracellular heterogeneity in the MICUs, which might be relevant for specialization of cells in complex organs. MICU1 loss was shown to be followed by secondary mtCU composition changes, which might be either adaptive or maladaptive, however the temporal ordering of these changes and others beyond the mtCU itself are not known. Whereas MICU1 loss-induced cell injury has been attributed to mitochondrial Ca2+ overload, our preliminary findings point to the importance of other contributors, namely mitochondrial reactive oxygen species and structural alterations. Thus, delineating the mechanisms by which MICUs contribute to the inter-and intracellular organization of Ca2+ signaling and the stability of mitochondrial structure and function are of vast significance. Here we pose the hypothesis that MICUs are important for individual cells’ Ca2+ signal fingerprints, for redox homeostasis and for fusion-fission and cristae dynamics of the mitochondria. To test these ideas, we have developed novel assays and assembled an array of cell and mouse genetic models. Our specific aims are to determine (1) if MICU1 gating of the mtCU creates intracellular heterogeneity in Ca2+ signaling; (2) if the control of mtCU gating by MICUs is relevant for mitochondrial redox homeostasis; (3) if MICU1, MICU2 and MICU3 contribute to the control of mitochondrial fusion-fission dynamics and cristae shaping and these contributions depend on the gating of the mtCU. Completion of these aims will provide clues to the mechanisms by which MICUs support mitochondrial membrane dynamics and signaling and to the pathogenesis initiated by perturbing mtCU structure and function.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).