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The core components of MCU complex

- MCU protein

MCU is the pore forming domain of the uniporter. Its size is about a 40kDa composed of two
coiled-coil domains, and two transmembrane domains separated by a short hydrophilic loop
enriched in acidic residues.

- MCUb domain

33 kDa protein with 50% similarity to MCU, and it has two transmembrane domains with its N-
and C-termini facing the inner membrane space (IMS). MCUb overexpression reduces
mitochondrial Ca2+ uptake.


Essential MCU Regulator (MCU) is 10 kDa protein with a single transmembrane domain with a
highly acidic C-terminus located in inner mitochondrial membrane. EMRE interacts with
MICU1 at IMS and with MCU oligomers in the inner membrane, thus EMRE acts as a bridge
between the Ca2+ sensing activity of MICU1/2 and the channel properties of MCU.

2. MCU-associated regulators


54 kDa single-pass membrane that contains two highly conserved EF-hand Ca2+ binding
domains. MICU1 limits Ca2+ entry via MCU when the intracellular Ca2+ concentration is low
(< 3uM). In contrast, MICU1 has no effect on uniporter-mediated Ca2+ uptake at higher Ca2+
concentration in intermembrane space. It was concluded that MICU1 provides a gatekeeping
function to minimize uniporter activity under resting conditions, protecting mitochondria from
chronic Ca2+ overload. This mechanism, rather than intrinsic low Ca2+ affinity of MCU,
accounts for the apparent low Ca2+ affinity of the uniporter.


MICU2 forms an obligate heterodimer with MICU1 that interact with MCU in the DIME loop,
thus facing the intermembrane space. It has 25% sequence identity with MICU1. At low [Ca2+],
the prevailing inhibitory effect of MICU2 ensures minimal Ca2+ accumulation in the presence of
a very large driving force for cation accumulation, thus preventing the deleterious effects of
Ca2+ cycling and matrix overload. As soon as extramitochondrial [Ca2+] increases, Ca2+-
dependent MICU2 inhibition and MICU1 activation guarantees the prompt initiation of rapid
mitochondrial Ca2+ accumulation, thus stimulating aerobic metabolism and increasing ATP


40 kDa protein that contains two transmembrane domains and one coiled-coil region with N- and
C- terminifacing the intermemrane space. Its silencing abrogates mitochondrial Ca2+ uptake
while its overexpression enhances MCU activity. This protein was shown to interact with MCU,
although mass spectrometry of MCU interactors failed to identify MCUR1. MCUR1 was not
detected in a proteomics study of the uniporter complex associated with immunoprecipitated
epitope-tagged MCU in HEK-293 cells. Thus, additional studies are required to establish the
mechanisms and role of MCUR1 in the uniporter complex.

To understand the mechanism:

The current model for the regulation of uniporter activity by calcium is shown in schematic
form. a | When calcium concentration ([Ca2+]) in the intermembrane space is low, mitochondrial
calcium uptake protein 1 (MICU1) and MICU2 inhibit calcium uptake through the uniporter. b |
When [Ca2+] rises, such as during a signalling event, the inhibition is relieved and calcium is
transported through the uniporter. The red triangles indicate calcium ions. As the mechanism by
which MCUb regulates uniporter activity is currently unclear and MCUb is dispensable for
uniporter activity, and MICU3 is largely expressed in the central nervous system, these proteins
have not been depicted in this model.

In resting condition mitochondrial calcium uptake is controlled by a multiprotein complex that

can be composed by MCU and MCUb (the channel forming subunits) together with EMRE,
MICU1, and MICU2 (other components are omitted for the sake of clarity). In these conditions,
MICU1/MICU2 heterodimers act as MCU gatekeeper, thanks to the prevailing inhibitory effect
of MICU2, thus preventing vicious calcium cycles and energy sink. As soon as calcium signaling
is activated, the increase in extramitochondrial [Ca2+] induces a conformational change in the
whole dimer that releases MICU2-dependent inhibition and triggers MICU1-mediated
enhancement of MCU channeling activity.