Abstract
MICU1 and MICU2 are the main regulators of the mitochondrial Ca2+-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 [Ca2+] ([Ca2+]c), though its effects decrease as [Ca2+]c is increased and disappear above 7μM. 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 Ca2+ 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 [Ca2+]c, separate and kinetically different from that of MICU2. On the other hand, we and others have shown previously that MICU1 activates MCU at [Ca2+]c above 2.5μM. Thus, MICU1 has a double role in MCU regulation, inhibitory at low [Ca2+]c and activatory at high [Ca2+]c.
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