Functional roles of MICU1 and MICU2 in mitochondrial Ca(2+) uptake
- Biochim Biophys Acta. 2016 Jun;1858(6):1110-7. doi: 10.1016/j.bbamem.2016.02.022.
- 1. Instituto de Biología y Genética Molecular (IBGM), Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Ramón y Cajal, 7, E-47005 Valladolid, Spain.
- 2. Instituto de Biología y Genética Molecular (IBGM), Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Ramón y Cajal, 7, E-47005 Valladolid, Spain. Electronic address: [email protected].
MICU1 and MICU2 are the main regulators of the mitochondrial CA(2+)-uniporter (MCU), but their precise functional role is still under debate. We show here that MICU2 behaves as a pure inhibitor of MCU at low cytosolic [CA(2+)] ([CA(2+)]c), though its effects decrease as [CA(2+)]c is increased and disappear above 7 μM. Regarding MICU1, studying its effects is more difficult because knockdown of MICU1 leads also to loss of MICU2. However, while knockdown of MICU2 induces only a persistent increase in mitochondrial CA(2+) uptake, knockdown of MICU1 also induces a peculiar use-dependent transient activation of MCU that cannot be attributed to the parallel loss of MICU2. Therefore, MICU1 is endowed with a specific inhibitory effect on MCU at low [CA(2+)]c, separate and kinetically different from that of MICU2. On the Other hand, we and Others have shown previously that MICU1 activates MCU at [CA(2+)]c above 2.5 μM. Thus, MICU1 has a double role in MCU regulation, inhibitory at low [CA(2+)]c and activatory at high [CA(2+)]c.