Functional roles of MICU1 and MICU2 in mitochondrial Ca 2+ uptake

Abstract

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.

MICU2 Restricts Spatial Crosstalk between InsP 3 R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU

“…In this model, MICU2 is the “true gatekeeper”, inhibiting the channel in its Ca 2+ -free form, whereas cooperative channel-activation requires Ca 2+ binding to MICU1, as well as to MICU2, to relieve channel inhibition. Alternatively, it has been suggested that both MICU1 and MICU2 play roles in gatekeeping, with MICU2 having no role in channel activation (Matesanz-Isabel et al, 2016). Finally, it has been suggested that both MICU1 and MICU2 contribute to setting the threshold for MCU activation (Kamer and Mootha, 2014).…”

Expression of MICU1 after experimental focal cerebral ischemia in adult rats

“…That MICU1 is a key regulator of MCU implicates MICU1 serving a pivotal role in the initial progression of stroke. In particular, MICU1 can activate MCU at high [Ca 2+ ] c [3], which can subsequently promote MCU-induced mitochondrial Ca 2+ uptake and ultimately cell death. However, this remains speculative as we have not yet established that the upregulation of MICU1 expression directly modulates MCAO onset and progression.…”

“…In view of the reported interaction between MICU1 and MCU, whereby MICU1 activates MCU at high [Ca 2+ ] c [3], we advanced the hypothesis that if indeed MICU1 is involved in the early pathogenesis of stroke, then MICU1 upregulation should be detected acutely in discrete regions of the ischemic stroke brain. Thus, we examined here the expression of MICU1 both at protein and mRNA levels at the acute stages of experimentally induced ischemic stroke in animals.…”

“…Mitochondrial Ca 2+ uptake 1 (MICU1) has been demonstrated to be a key regulator of MCU [3]. This MICU1 regulation (albeit inhibition) of MCU activation occurs at low cytosolic free Ca2+ concentration [Ca 2+ ] c , while MICU1 as an activator of MCU ensues at high [Ca 2+ ] c (2.5 μM) [3]. Interestingly, upregulated expression of MCU and increased [Ca 2+ ] c accompany the early stages of cerebral ischemic damage [2,3].…”

“…Previous studies have demonstrated that the mitochondrial calcium uniporter (MCU), which possesses two transmembrane domains and forms tetrameric highly specific mitochondrial Ca 2+ channels, is responsible for the mitochondrial Ca 2+ uptake [2]. Mitochondrial Ca 2+ uptake 1 (MICU1) has been demonstrated to be a key regulator of MCU [3]. This MICU1 regulation (albeit inhibition) of MCU activation occurs at low cytosolic free Ca2+ concentration [Ca 2+ ] c , while MICU1 as an activator of MCU ensues at high [Ca 2+ ] c (2.5 μM) [3].…”