Mitochondrial calcium (Ca2+) signaling has long been known to regulate diverse cellular functions, ranging from ATP production via oxidative phosphorylation, to cytoplasmic Ca2+ signaling to apoptosis. Central to mitochondrial Ca2+ signaling is the mitochondrial Ca2+ uniporter complex (MCUC) which enables Ca2+ flux from the cytosol into the mitochondrial matrix. Several pivotal discoveries over the past 15 years have clarified the identity of the proteins comprising MCUC. Here, we provide an overview of the literature on mitochondrial Ca2+ biology and highlight recent findings on the high-resolution structure, dynamic regulation, and new functions of MCUC, with an emphasis on publications from the last five years. We discuss the importance of these findings for human health and the therapeutic potential of targeting mitochondrial Ca2+ signaling.

Mitochondrial calcium (Ca2+) uptake was first observed as an in vitro phenomenon in the early 1960s [1,2]. It was quickly recognized as an important regulator of mitochondrial bioenergetics through Ca2+-mediated activation of the TCA cycle. This foundational work paved the way for decades of research on the functions of mitochondrial Ca2+ uptake in physiology and diseases. Yet, the molecular identity of the uniporter remained a mystery for decades. The proteins responsible for mitochondrial Ca2+ influx into the mitochondrial matrix — the mitochondrial calcium uniporter (MCU) and its regulatory proteins — were identified over the last 13 years. These discoveries dramatically accelerated efforts to understand the regulation and function of mitochondrial Ca2+ uptake. Ca2+ influx across the inner mitochondrial membrane (IMM) is now recognized to govern numerous aspects of biology, ranging from ATP production via oxidative phosphorylation, to cytoplasmic Ca2+ signaling in a variety of tissues [3–6], to regulation of immunological synapses [7]. High mitochondrial matrix [Ca2+] can also lead to opening of the mitochondrial permeability transition pore (mPTP), a structure that is responsible for rapid release of Ca2+ and other small molecules from the mitochondrial matrix to the cytosol, which can cause cell death [8]. Mitochondrial Ca2+ signaling has also been found to play a significant role in human diseases including neurological disorders such as amyotrophic lateral sclerosis, Friedreich's ataxia, Charcot–Marie–Tooth disease [9], Alzheimer's disease [10], as well as heart failure [11] and lysosomal storage disorders [12].

The field of mitochondrial Ca2+ biology continues to advance rapidly. Here, we review recent publications centered on the MCU, with an emphasis on its structure, novel regulatory mechanisms, and its emerging roles in development, mitochondrial diseases and immunity. We contextualize these findings in the broader field, while emphasizing publications from the past five years. Many excellent reviews concerning the biology of mitochondrial Ca2+ signaling were published within this same time frame. Of note are those concerning the mechanisms of mitochondrial Ca2+ signaling in health and disease, as well as those exploring the role of mitochondrial Ca2+ signaling in cardiac disease, diabetes, cellular senescence, cancer, and neurodegeneration. We encourage the reader to pursue these reviews to gain an even deeper understanding of this rich field [13–19].

To maintain homeostasis, mitochondria must precisely balance the influx, sequestration, and release of Ca2+ into and from the mitochondrial matrix. Characterizing the machinery and chemistry central to these processes has clarified the regulation and biological implications of mitochondrial Ca2+ cycling and signaling. The main players of mitochondrial Ca2+ homeostasis are shown in Figure 1 and described in more detail below.

Mechanisms of mitochondrial Ca2+ influx, efflux, and sequestration.

Figure 1.
Mechanisms of mitochondrial Ca2+ influx, efflux, and sequestration.

Mitochondria are organelles with an outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). Ca2+ ions likely diffuse through the OMM via VDAC proteins. Bulk transport of Ca2+ across the IMM and into the mitochondrial matrix requires the mitochondrial calcium uniporter complex (MCUC), a highly selective ion channel. NCLX, a Ca2+/Na+ exchanger, enables the majority of Ca2+ efflux from the mitochondria. Calcium phosphate deposits within the mitochondria sequester Ca2+ and may serve as Ca2+ reservoirs that can be mobilized if needed.

Figure 1.
Mechanisms of mitochondrial Ca2+ influx, efflux, and sequestration.

Mitochondria are organelles with an outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). Ca2+ ions likely diffuse through the OMM via VDAC proteins. Bulk transport of Ca2+ across the IMM and into the mitochondrial matrix requires the mitochondrial calcium uniporter complex (MCUC), a highly selective ion channel. NCLX, a Ca2+/Na+ exchanger, enables the majority of Ca2+ efflux from the mitochondria. Calcium phosphate deposits within the mitochondria sequester Ca2+ and may serve as Ca2+ reservoirs that can be mobilized if needed.

Close modal

Mechanisms of influx

Mitochondrial Ca2+ uptake from the cytosol to the mitochondrial matrix faces two primary physical barriers: the outer mitochondrial membrane (OMM) and the IMM. Ca2+ transport across the OMM remains poorly understood as the OMM is not believed to have a specific Ca2+ transporter [20]. Rather, the voltage-dependent anion channel (VDAC) is believed to passively permit the diffusion of metabolites and solutes such as Ca2+. VDAC was recently demonstrated to form multi-protein complexes with the Ca2+ channels of other organelles, thus facilitating highly efficient Ca2+ transfer through the OMM [21].

Once past the OMM, the vast majority of Ca2+ travels from the intermembrane space (IMS) to the mitochondrial matrix via rapid bulk entry through the MCU. MCU is a pore-forming protein that resides in the IMM and is the eponymous protein of the mitochondrial calcium uniporter complex (MCUC). MCU-facilitated Ca2+ flux is dependent on mitochondrial membrane potential. The uniporter is a Ca2+ selective channel, and patch-clamp experiments of the IMM reveal that it has a Ca2+ affinity of 2 nM or less [22].

Additional core MCUC proteins include Mitochondrial Calcium Uptake (MICU) homologs MICU1–3, Essential MCU Regulator (EMRE), and MCUb. The MICU proteins play distinct, crucial roles in setting the threshold for uniporter Ca2+ uptake and its potentiation. They also contribute to specific Ca2+ regulation of the channel through their EF-hand Ca2+-binding domains [23–30]. The consensus of the field is that, when the cytosolic [Ca2+] is low, MICU1 blocks the MCU pore to prevent mitochondrial Ca2+ overload [23,27,28,31]. When IMS [Ca2+] increases, Ca2+ binds to the EF-hands of the MICU proteins. MICU1 — which forms a disulfide-bonded heterodimer with either MICU2 or MICU3 — then dissociates from MCU, enabling Ca2+ conductance. Recent structural work supports this consensus, as discussed in detail below. EMRE, a small transmembrane protein, is required for both MCU–MICU1 interaction and Ca2+ conductance through MCU [32–34]. MCUb is a paralog of MCU, but it does not form a functional Ca2+ channel and seems to have a negative regulatory role in the MCUC. MICU3, a MICU1 paralog, is mostly found in brain tissue and enhances Ca2+ uptake in neuronal mitochondria [35] (Figure 2).

The mitochondrial calcium uniporter complex.

Figure 2.
The mitochondrial calcium uniporter complex.

The mitochondrial calcium uniporter complex (MCUC) is composed of membrane proteins MCU, MCUb, EMRE and IMS-localized proteins MICU1 and MICU2. MCU is the pore-forming protein and requires EMRE to form a functional channel in multicellular and some unicellular organisms. The incorporation of MCUb into the MCUC modulates mitochondrial Ca2+ flux and prevents mitochondrial Ca2+ overload. The MICU proteins — MICU1, MICU2, and MICU3 — block the entrance of Ca2+ into the pore, except during Ca2+ signaling events. During signaling events, the MICU proteins dissociate from the MCUC pore, remaining tethered via MICU1–EMRE binding. MICU1 forms a disulfide-bonded heterodimer with either MICU2 or MICU3, though MICU3 has only been identified in brain tissue. Arrows indicate the presence or absence of Ca2+ transport, with MCUC illustrated in a closed, non-conductive conformation (left) or an open, Ca2+-conducting conformation (right).

Figure 2.
The mitochondrial calcium uniporter complex.

The mitochondrial calcium uniporter complex (MCUC) is composed of membrane proteins MCU, MCUb, EMRE and IMS-localized proteins MICU1 and MICU2. MCU is the pore-forming protein and requires EMRE to form a functional channel in multicellular and some unicellular organisms. The incorporation of MCUb into the MCUC modulates mitochondrial Ca2+ flux and prevents mitochondrial Ca2+ overload. The MICU proteins — MICU1, MICU2, and MICU3 — block the entrance of Ca2+ into the pore, except during Ca2+ signaling events. During signaling events, the MICU proteins dissociate from the MCUC pore, remaining tethered via MICU1–EMRE binding. MICU1 forms a disulfide-bonded heterodimer with either MICU2 or MICU3, though MICU3 has only been identified in brain tissue. Arrows indicate the presence or absence of Ca2+ transport, with MCUC illustrated in a closed, non-conductive conformation (left) or an open, Ca2+-conducting conformation (right).

Close modal

Structural and biochemical studies have shown that MCU and its associated proteins form the MCUC, a large holocomplex whose structure and interactions are discussed in detail below. Two other IMM proteins, Mitochondrial Calcium Uniporter Regulator 1 (MCUR1) and Solute Carrier 25A23, also regulate the activity of the uniporter despite not being a part of the core complex [36,37]. MCUR1 is a scaffold protein that binds to MCU and EMRE and is required for MCUC assembly. SLC25A23 augments mitochondrial Ca2+ uptake, however the exact mechanism of this regulation remains elusive.

Mechanisms of Ca2+ efflux and sequestration

Matrix Ca2+ is maintained at a far lower resting concentration than the concentration reached after a Ca2+ signaling event [38]. This regulation is crucial; excessive mitochondrial Ca2+ accumulation can be hazardous, as it can lead to mitochondrial Ca2+ overload or opening of the permeability transition pore [39]. To restore resting Ca2+ levels, exchangers and antiporters facilitate the exit of Ca2+ from mitochondria. The Na+/Ca2+ exchanger NCLX is the dominant Ca2+ efflux pathway [40]. NCLX is expressed on the IMM of many tissues, in an expression pattern similar to that of MCU [41,42]. Ca2+ ions are also stored as calcium phosphate deposits in the mitochondrial matrix. Fast sequestration of Ca2+ in the form of calcium phosphate after mitochondrial Ca2+ entry is thought to play an important role in reducing the concentration of free matrix [Ca2+]. These deposits are also thought to serve as Ca2+ reservoirs that can be mobilized if needed. Although the function of mitochondrial calcium phosphate deposits is still under debate, their visualization using cryo-scanning transmission electron tomography shows that these deposits form independently of MCU, disappear if mitochondrial membrane potential is lost, and do not preferentially form in mitochondria in a particular cellular location [43].

A remarkable series of studies have recently shed light on the structures of the individual proteins of the MCUC, as well as the uniporter holocomplex in its Ca2+-bound and Ca2+-free states [30,44–50]. By defining specific interactions of the uniporter proteins and identifying a lipid molecule that interacts with the uniporter channel, these publications have helped to develop a more refined model of uniporter regulation and the functions of its individual subunits.

In the wake of these publications and their predecessors, the following is clear: MCU is a transmembrane protein that spans the IMM and contains two transmembrane-spanning helices, TM1 and TM2. TM2 of MCU forms the protein's Ca2+-conducting pore. Although MCU was known to oligomerize prior to 2018 [32,51], cryo-EM structures established the presence of a ‘dimer of dimer' structure composed of four MCU protomers [44–47], with different symmetric arrangements of the soluble and transmembrane domains [47]. There are four EMRE subunits per functional channel. Structurally, EMRE participates in the formation of functional channels by interacting with MCU at the matrix channel opening. This interaction stabilizes a region at the inner leaflet of the IMM, which is otherwise flexible. This region is proposed to occlude the matrix side of the Ca2+ pore, preventing escape of Ca2+ ions into the matrix and regulating channel gating through binding-induced structural changes in the channel [50,52]. Related work from our laboratory independently validated several of these structural findings biochemically, by using a suite of protein chimeras composed of domains from H. sapiens MCU (HsMCU) and D. discoideum MCU (DdMCU) [53]. D. discoideum MCU is functional in the absence of EMRE, which enabled us to characterize the aspects of HsMCU that make it dependent on EMRE for Ca2+ conductance. This work led to the identification of a 10-amino acid region in HsMCU that renders it EMRE-dependent; we termed this region EMRE dependence domain (EDD). This biochemically identified EDD region overlaps with a 6-amino acid stretch first identified by Wang et al. [50] in a mammalian EMRE–MCU structure that they show is important for EMRE function.

A second function of EMRE is facilitating the interaction of MICU1 with MCU through EMRE's positively charged DDD domain that faces the IMS. Using structural data from the MICU1–MICU2 heterodimer and in vitro binding experiments, Wu et al. [49] showed that the DDD domain interacts with a Ca2+-induced alkaline stretch in MICU1. This Ca2+-enhanced interaction between EMRE and MICU1 is thought to prevent complete dissociation of MICU1 from the complex in the presence of Ca2+. Two publications also suggested another important function of the EMRE–MICU1 interaction: potentiation of uniporter activity [30,54]. The authors propose that, by binding to EMRE when Ca2+ is present, MICU1 alters MCU–EMRE interaction, which results in increased uniporter conductance.

The activity of the uniporter varies across physiological conditions and cell types [55]. Recent work highlighted the importance of two primary modes of fine-tuning uniporter activity: steady state differences in the expression of MCUC proteins across tissues; and regulation of MCUC proteins in response to stress, disease, or other alterations to cellular or organismal physiology.

MCU and MICU1 are posttranslationally modified in response to various stimuli, which lead to changes in uniporter activity and have been reviewed before [56]. Here, we focus on new research indicating that changes to uniporter subunit composition or altered stability of the complex is a novel mode of uniporter regulation. Such changes often happen at the level of individual complex proteins, and can have dramatic, long-lasting effects on cellular and tissue wide Ca2+ signaling and metabolism. For example, during chronic stress, increased MCUb incorporation into the complex limits mitochondrial Ca2+ overload and counteracts mitochondrial damage, as seen in mice in response to cardiac injury [57]. Consistent with this observation, Huo et al. [58] demonstrated that cardiomyocyte-specific MCUb knockout mice exhibited increased pathological cardiac remodeling and infarct expansion following ischemic injury. This same group found the inverse in cardiomyocyte specific MCUb overexpressing mice, highlighting the importance of proper uniporter composition for homeostasis.

A similar mechanism of altered uniporter composition is observed in failing human heart tissue. The relative mRNA abundance of MICU1 to MCU is tissue-specific and is particularly low in cardiac muscle. During heart failure, MICU1/2 expression increases, while MCU expression stays the same. This altered composition likely changes the gating and activity of the uniporter in failing human hearts and may contribute to decreased cardiac contractile function in heart failure [59]. MICU3 is another uniporter regulatory protein whose presence in the complex substantially alters the physiological performance of specific tissues. MICU3 is a paralog of MICU1 and MICU2. It is mostly found in the brain and binds specifically to MICU1 to enhance Ca2+ uptake [35]. If MICU3 is silenced in primary cortical neurons, the Ca2+ signals spurred by synaptic activity are impaired. Finally, increased MICU1 expression and ensuing changes in Ca2+ signaling and metabolism are important for fibroblast to myofibroblast differentiation [60].

The precise regulation of EMRE has important consequences for human health. Under normal physiological conditions, EMRE that does not complex with MCU is rapidly degraded by the m-AAA protease [61]. This process is essential to maintaining the balance of MCU–EMRE that are assembled with an adequate ratio of MICU1/MICU2 ‘gatekeeper’ subunits [62]. Mutations in mitochondrial m-AAA proteases, which are linked to neurodegeneration in spinocerebellar ataxia (SCA28) and hereditary spastic paraplegia (HSP7), lead to accumulation of EMRE and formation of excess MCU–EMRE complexes that are not gated by MICUs. This eventually leads to unregulated mitochondrial Ca2+ entry and overload. This has been proposed to contribute to neurodegeneration in these debilitating diseases.

The stability of MCU is also carefully regulated, as recently shown by two elegant studies. In 2020, using functional experiments in a yeast heterologous uniporter expression system, Ghosh et al. [63] showed that cardiolipin plays an essential role in stabilizing MCU. This finding may clarify the pathologically low cardiolipin and uniporter levels observed in patients with Barth syndrome, a disease characterized by partial loss of cardiolipin. Furthermore, Dr. Chaudhuri and coworkers discovered a novel link between OXPHOS function and MCU. In healthy cells, reactive oxygen species that leak from Complex I of the electron transport chain damage MCU and lead to its degradation. In Complex I deficiency, MCU is stabilized, and the number of functional uniporter channels increases, leading to an increase in overall MCUC activity. Most importantly, the authors showed that uniporter function prolongs survival of OXPHOS-deficient mice and Drosophila, thereby identifying a previously unknown function for the uniporter [64].

Targeted perturbation of mitochondrial Ca2+ flux in animal models and phenotypes of patients with uniporter gene mutations highlight the importance of this pathway in development, immunity, neuromuscular system and metabolic health. Likely due to highly tissue-specific nature of Ca2+ signaling and mitochondrial functions, uniporter activity has been shown to regulate distinct pathways across different tissue types. Despite this functional diversity, altered uniporter regulation fundamentally produces a phenotype through either altered metabolic regulation, and/or altered cellular Ca2+ signaling. Here, we non-exhaustively highlight recent findings on the physiological roles of MCU.

Emerging roles of the uniporter in early development and differentiation

The first report of MCU knockout (KO) mice was somewhat of a surprise for mitochondrial community: loss of MCU was compatible with life, but only on a mixed background [65]. Since then, the same phenotype of viability on a mixed background has been shown for EMRE KO mice [66]. MCU loss is also tolerated in the fly and the worm [55,67]. Despite being viable, loss of MCU causes reduced viability in the mouse. The KO mice are observed at much lower ratios than expected from a heterozygous mating [68]. This suggests the presence of modifiers (genetic or environmental) that allow survival of animals past a certain developmental stage in the absence of mitochondrial Ca2+ uptake. Important roles for mitochondrial Ca2+ uptake in early development were recently shown in different model organisms and systems. In Xenopus eggs, early cell divisions after fertilization require ROS generated by the mitochondria, which is fueled by MCU-mediated mitochondrial Ca2+ uptake [69]. Modulation of MCU activity is also observed in human embryonic stem cells (hESCs): repression of MICU1 by Foxd1 is essential for proper differentiation of hESCs into induced pluripotent stem cells [70] (hiPSCs). The authors in this study conclude that the presence of MICU1 modulates periodic cytosolic Ca2+ oscillations necessary for differentiation. These new roles of the uniporter in early development help explain the viability (albeit low) of MCU KO animals on a mixed background. Nevertheless, how MCU KO animals survive, and what type of compensatory changes take place in these survivors, are still unknown.

Although no MCU mutation has ever been identified in humans, a recent preprint by Bulthuis et al. [71] reported two patients with EMRE mutations that lead to a loss of EMRE protein. Muscle breakdown was a common phenotype observed in both patients, who otherwise showed diverse symptoms. In addition, several patients with MICU1 mutations have been reported to date (OMIM #615673), most of which present with neuromuscular problems. A neuron-specific MICU1 KO mouse model recapitulates the phenotypes observed in patients and whole body MICU1 KO mice, suggesting that neuronal abnormalities are the main cause of the observed phenotypes in patients [72]. Nevertheless, phenotypic diversity observed in humans again underlines the importance of other modifiers and compensatory mechanisms in mitochondrial Ca2+ regulation. For example, the appearance and bodyweight of MICU1 KO mice become more similar to wildtype mice over time due to down-regulation of EMRE expression [27].

Emerging tissue-specific roles of the uniporter

Several recent studies highlight the diverse, tissue-specific functions of the uniporter. They also point to a need for further research on uniporter regulation and function, as several contradictory phenotypes associated with the uniporter have been reported. For example, in a 2020 publication, Flicker et al. [73] generated a brown adipose tissue (BAT)-specific MCU KO mouse and reported that MCU is not required for brown fat energetics. In contrast, Xue et al. [74] found that in the BAT, the uniporter function is important for thermogenesis in response to cold. The authors suggested that these disparities are due to the differences in the genetic background of the mice used in these two papers, but they could also stem from experimental differences such as fasting before cold exposure in the second study. In addition, several papers reported contradicting phenotypes associated with loss of uniporter function in the heart. As proposed by Garbincius et al. [75], some of these differences can be attributed to cellular adaptations in response to chronic loss of uniporter function but are absent from its acute inhibition.

The importance of metabolism, mitochondria and cellular Ca2+ signaling for proper functioning of the innate immunity is well appreciated [76]. The uniporter sits at the intersection of these regulators, and several papers showed important roles of the uniporter in different aspects of cellular responses to pathogens. In neutrophils, activation of mitochondrial Ca2+ uptake stimulates cell polarization and chemotaxis, which are required for effective removal of pathogenic species [77]. In addition, increased uniporter function is associated with phagocytosis-induced activation of NLRP3 inflammasome in macrophages [78]. Conversely, reduced uniporter activity due to MCUb expression decreases inflammation in macrophages [79]. Moreover, in epithelial cells that express pathogenic cystic fibrosis receptor, bacterial infection activates NLRP3 in an MCU-dependent manner [80]. Even though MCU activation is associated with worse cellular outcomes and more pathogen survival in the literature so far, whether modulating its activity pharmacologically would be beneficial or damaging to the cells is likely to depend on many factors at play, such as the duration of infection and detrimental effects of prolonged inflammation.

Identification of the MCUC protein components accelerated research on numerous aspects of uniporter biology and led to exciting discoveries on the structure, regulation, and function of the uniporter, as well as its roles in diseases. Nevertheless, several fundamental questions about mitochondrial Ca2+ signaling and MCUC regulation at the level of transcription, post-transcription, translation, and posttranslation remain unanswered. For example, the presence of yet-uncharacterized, uniporter-independent mitochondrial Ca2+-entry pathways have been reported [81,82]. Identification of these pathways could alter our understanding of how mitochondrial Ca2+ signaling reflects and responds to mitochondrial and cellular needs. Furthermore, upstream signals that change MCUC protein transcription or the generation of alternative splice variants remain to be characterized and may help explain tissue-specific differences in uniporter function [83].

Finally, while mitochondrial Ca2+ signaling is generally considered necessary for proper mitochondrial and cellular health, the viability of MCU KO cells in mixed background mice suggests that the loss of uniporter function may be tolerated in normal tissues and may even have protective effects in the context of Ca2+-induced mitochondrial damage, as observed in hereditary ataxias. Though the therapeutic potential of MCUC inhibition is made uncertain by the diverse roles of mitochondrial Ca2+ flux in different tissues, and the cellular adaptations to altered uniporter function, the MCUC remains a promising therapeutic target. The field of mitochondrial Ca2+ signaling continues to develop rapidly and deepen our understanding of the mitochondria's role in health and disease. We look forward to what is to come.

The authors declare that there are no competing interests associated with the manuscript.

M.J.S.M. was supported by NIH grant 1F31AG072716-01A1. Y.S. is supported by NIH grant DP2ES032761 and is a Pew Biomedical Scholar.

We thank Timothy Locke and David Shechner for critical reading of the manuscript and suggestions.

BAT

brown adipose tissue

EDD

EMRE dependence domain

EMRE

essential MCU regulator

HsMCU

H. sapiens MCU

IMM

inner mitochondrial membrane

IMS

intermembrane space

KO

knockout

MCU

mitochondrial calcium uniporter

MCUC

mitochondrial calcium uniporter complex

MCUR1

mitochondrial calcium uniporter regulator 1

MICU

mitochondrial calcium uptake

OMM

outer mitochondrial membrane

VDAC

voltage-dependent anion channel

1
Deluca
,
H.F.
and
Engstrom
,
G.W.
(
1961
)
Calcium uptake by rat kidney mitochondria
.
Proc. Natl Acad. Sci. U.S.A.
47
,
1744
1750
2
Vasington
,
F.D.
and
Murphy
,
J.V.
(
1962
)
Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation
.
J. Biol. Chem.
237
,
2670
2677
3
Dedkova
,
E.N.
and
Blatter
,
L.A.
(
2013
)
Calcium signaling in cardiac mitochondria
.
J. Mol. Cell. Cardiol.
58
,
125
133
4
Kamer
,
K.J.
and
Mootha
,
V.K.
(
2015
)
The molecular era of the mitochondrial calcium uniporter
.
Nat. Rev. Mol. Cell Biol.
16
,
545
553
5
Nicholls
,
D.G.
(
2009
)
Mitochondrial calcium function and dysfunction in the central nervous system
.
Biochim. Biophys. Acta
1787
,
1416
1424
6
Rizzuto
,
R.
,
De Stefani
,
D.
,
Raffaello
,
A.
and
Mammucari
,
C.
(
2012
)
Mitochondria as sensors and regulators of calcium signalling
.
Nat. Rev. Mol. Cell Biol.
13
,
566
578
7
Quintana
,
A.
and
Hoth
,
M.
(
2012
)
Mitochondrial dynamics and their impact on t cell function
.
Cell Calcium
52
,
57
63
8
Giorgi
,
C.
,
Baldassari
,
F.
,
Bononi
,
A.
,
Bonora
,
M.
,
De Marchi
,
E.
,
Marchi
,
S.
et al (
2012
)
Mitochondrial Ca2+ and apoptosis
.
Cell Calcium
52
,
36
43
9
Rodriguez
,
L.R.
,
Lapena-Luzon
,
T.
,
Beneto
,
N.
,
Beltran-Beltran
,
V.
,
Pallardo
,
F.V.
,
Gonzalez-Cabo
,
P.
et al (
2022
)
Therapeutic strategies targeting mitochondrial calcium signaling: a new hope for neurological diseases?
Antioxidants (Basel)
11
,
165
10
Calvo-Rodriguez
,
M.
,
Hou
,
S.S.
,
Snyder
,
A.C.
,
Kharitonova
,
E.K.
,
Russ
,
A.N.
,
Das
,
S.
et al (
2020
)
Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease
.
Nat. Commun.
11
,
2146
11
Boyman
,
L.
,
Williams
,
G.S.
and
Lederer
,
W.J.
(
2015
)
The growing importance of mitochondrial calcium in health and disease
.
Proc. Natl Acad. Sci. U.S.A.
112
,
11150
11151
12
Peng
,
W.
,
Wong
,
Y.C.
and
Krainc
,
D.
(
2020
)
Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal Trpml1
.
Proc. Natl Acad. Sci. U.S.A.
117
,
19266
19275
13
Ahumada-Castro
,
U.
,
Puebla-Huerta
,
A.
,
Cuevas-Espinoza
,
V.
,
Lovy
,
A.
and
Cardenas
,
J.C.
(
2021
)
Keeping zombies alive: the Er-mitochondria Ca2+ transfer in cellular senescence
.
Biochim. Biophys. Acta Mol. Cell Res.
1868
,
119099
14
Alevriadou
,
B.R.
,
Patel
,
A.
,
Noble
,
M.
,
Ghosh
,
S.
,
Gohil
,
V.M.
,
Stathopulos
,
P.B.
et al (
2021
)
Molecular nature and physiological role of the mitochondrial calcium uniporter channel
.
Am. J. Physiol. Cell Physiol.
320
,
C465
C482
15
Arnst
,
N.
,
Redolfi
,
N.
,
Lia
,
A.
,
Bedetta
,
M.
,
Greotti
,
E.
and
Pizzo
,
P.
(
2022
)
Mitochondrial Ca2+ signaling and bioenergetics in Alzheimer's disease
.
Biomedicines
10
,
3025
16
Boyman
,
L.
,
Greiser
,
M.
and
Lederer
,
W.J.
(
2021
)
Calcium influx through the mitochondrial calcium uniporter holocomplex, Mcu(Cx)
.
J. Mol. Cell. Cardiol.
151
,
145
154
17
Calvo-Rodriguez
,
M.
and
Bacskai
,
B.J.
(
2021
)
Mitochondria and calcium in Alzheimer's disease: from cell signaling to neuronal cell death
.
Trends Neurosci.
44
,
136
151
18
Modesti
,
L.
,
Danese
,
A.
,
Angela Maria Vitto
,
V.
,
Ramaccini
,
D.
,
Aguiari
,
G.
,
Gafa
,
R.
et al (
2021
)
Mitochondrial Ca2+ signaling in health, disease and therapy
.
Cells
10
,
1317
19
Murphy
,
E.
and
Steenbergen
,
C.
(
2021
)
Regulation of mitochondrial Ca2+ uptake
.
Annu. Rev. Physiol.
83
,
107
126
20
Hajnoczky
,
G.
,
Csordas
,
G.
and
Yi
,
M.
(
2002
)
Old players in a new role: mitochondria-associated membranes, Vdac, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria
.
Cell Calcium
32
,
363
377
21
Rosencrans
,
W.M.
,
Rajendran
,
M.
,
Bezrukov
,
S.M.
and
Rostovtseva
,
T.K.
(
2021
)
Vdac regulation of mitochondrial calcium flux: from channel biophysics to disease
.
Cell Calcium
94
,
102356
22
Kirichok
,
Y.
,
Krapivinsky
,
G.
and
Clapham
,
D.E.
(
2004
)
The mitochondrial calcium uniporter is a highly selective ion channel
.
Nature
427
,
360
364
23
Csordas
,
G.
,
Golenar
,
T.
,
Seifert
,
E.L.
,
Kamer
,
K.J.
,
Sancak
,
Y.
,
Perocchi
,
F.
, et al (
2013
)
Micu1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter
.
Cell Metab.
17
,
976
987
24
De La Fuente
,
S.
,
Matesanz-Isabel
,
J.
,
Fonteriz
,
R.I.
,
Montero
,
M.
and
Alvarez
,
J.
(
2014
)
Dynamics of mitochondrial Ca2+ uptake in micu1-knockdown cells
.
Biochem. J.
458
,
33
40
25
Foskett
,
J.K.
and
Madesh
,
M.
(
2014
)
Regulation of the mitochondrial Ca2+ uniporter by Micu1 and Micu2
.
Biochem. Biophys. Res. Commun.
449
,
377
383
26
Kamer
,
K.J.
,
Sancak
,
Y.
,
Fomina
,
Y.
,
Meisel
,
J.D.
,
Chaudhuri
,
D.
,
Grabarek
,
Z.
et al (
2018
)
Micu1 imparts the mitochondrial uniporter with the ability to discriminate between Ca2+ and Mn2+
.
Proc. Natl Acad. Sci. U.S.A.
115
,
E7960
E7969
27
Liu
,
J.C.
,
Liu
,
J.
,
Holmstrom
,
K.M.
,
Menazza
,
S.
,
Parks
,
R.J.
,
Fergusson
,
M.M.
, et al (
2016
)
Micu1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload
.
Cell Rep.
16
,
1561
1573
28
Perocchi
,
F.
,
Gohil
,
V.M.
,
Girgis
,
H.S.
,
Bao
,
X.R.
,
Mccombs
,
J.E.
,
Palmer
,
A.E.
et al (
2010
)
Micu1 encodes a mitochondrial EF hand protein required for Ca2+ uptake
.
Nature
467
,
291
296
29
Plovanich
,
M.
,
Bogorad
,
R.L.
,
Sancak
,
Y.
,
Kamer
,
K.J.
,
Strittmatter
,
L.
,
Li
,
A.A.
, et al (
2013
)
Micu2, a paralog of Micu1, resides within the mitochondrial uniporter complex to regulate calcium handling
.
PLos ONE
8
,
e55785
30
Zhuo
,
W.
,
Zhou
,
H.
,
Guo
,
R.
,
Yi
,
J.
,
Zhang
,
L.
,
Yu
,
L.
et al (
2021
)
Structure of intact human Mcu supercomplex with the auxiliary Micu subunits
.
Protein Cell
12
,
220
229
31
Pinton
,
P.
,
Giorgi
,
C.
,
Siviero
,
R.
,
Zecchini
,
E.
and
Rizzuto
,
R.
(
2008
)
Calcium and apoptosis: Er-mitochondria Ca2+ transfer in the control of apoptosis
.
Oncogene
27
,
6407
6418
32
Kovacs-Bogdan
,
E.
,
Sancak
,
Y.
,
Kamer
,
K.J.
,
Plovanich
,
M.
,
Jambhekar
,
A.
,
Huber
,
R.J.
et al (
2014
)
Reconstitution of the mitochondrial calcium uniporter in yeast
.
Proc. Natl Acad. Sci. U.S.A.
111
,
8985
8990
33
Sancak
,
Y.
,
Markhard
,
A.L.
,
Kitami
,
T.
,
Kovacs-Bogdan
,
E.
,
Kamer
,
K.J.
,
Udeshi
,
N.D.
, et al (
2013
)
Emre is an essential component of the mitochondrial calcium uniporter complex
.
Science
342
,
1379
1382
34
Tsai
,
M.F.
,
Phillips
,
C.B.
,
Ranaghan
,
M.
,
Tsai
,
C.W.
,
Wu
,
Y.
,
Willliams
,
C.
et al (
2016
)
Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex
.
eLife
5
,
e15545
35
Patron
,
M.
,
Granatiero
,
V.
,
Espino
,
J.
,
Rizzuto
,
R.
and
De Stefani
,
D.
(
2019
)
Micu3 is a tissue-specific enhancer of mitochondrial calcium uptake
.
Cell Death Differ.
26
,
179
195
36
Hoffman
,
N.E.
,
Chandramoorthy
,
H.C.
,
Shanmughapriya
,
S.
,
Zhang
,
X.Q.
,
Vallem
,
S.
,
Doonan
,
P.J.
, et al (
2014
)
Slc25a23 augments mitochondrial Ca2+ uptake, interacts with Mcu, and induces oxidative stress-mediated cell death
.
Mol. Biol. Cell
25
,
936
947
37
Tomar
,
D.
,
Dong
,
Z.
,
Shanmughapriya
,
S.
,
Koch
,
D.A.
,
Thomas
,
T.
,
Hoffman
,
N.E.
, et al (
2016
)
Mcur1 is a scaffold factor for the Mcu complex function and promotes mitochondrial bioenergetics
.
Cell Rep.
15
,
1673
1685
38
Finkel
,
T.
,
Menazza
,
S.
,
Holmstrom
,
K.M.
,
Parks
,
R.J.
,
Liu
,
J.
,
Sun
,
J.
et al (
2015
)
The ins and outs of mitochondrial calcium
.
Circ. Res.
116
,
1810
1819
39
Parks
,
R.J.
,
Murphy
,
E.
and
Liu
,
J.C.
(
2018
)
Mitochondrial permeability transition pore and calcium handling
.
Methods Mol. Biol.
1782
,
187
196
40
Assali
,
E.A.
,
Jones
,
A.E.
,
Veliova
,
M.
,
Acin-Perez
,
R.
,
Taha
,
M.
,
Miller
,
N.
, et al (
2020
)
Nclx prevents cell death during adrenergic activation of the brown adipose tissue
.
Nat. Commun.
11
,
3347
41
Boyman
,
L.
,
Williams
,
G.S.
,
Khananshvili
,
D.
,
Sekler
,
I.
and
Lederer
,
W.J.
(
2013
)
Nclx: the mitochondrial sodium calcium exchanger
.
J. Mol. Cell. Cardiol.
59
,
205
213
42
Palty
,
R.
,
Silverman
,
W.F.
,
Hershfinkel
,
M.
,
Caporale
,
T.
,
Sensi
,
S.L.
,
Parnis
,
J.
, et al (
2010
)
Nclx is an essential component of mitochondrial Na+/Ca2+ exchange
.
Proc. Natl Acad. Sci. U.S.A.
107
,
436
441
43
Wolf
,
S.G.
,
Mutsafi
,
Y.
,
Dadosh
,
T.
,
Ilani
,
T.
,
Lansky
,
Z.
,
Horowitz
,
B.
et al (
2017
)
3D visualization of mitochondrial solid-phase calcium stores in whole cells
.
Elife
6
,
e29929
44
Baradaran
,
R.
,
Wang
,
C.
,
Siliciano
,
A.F.
and
Long
,
S.B.
(
2018
)
Cryo-Em structures of fungal and metazoan mitochondrial calcium uniporters
.
Nature
559
,
580
584
45
Fan
,
C.
,
Fan
,
M.
,
Orlando
,
B.J.
,
Fastman
,
N.M.
,
Zhang
,
J.
,
Xu
,
Y.
et al (
2018
)
X-ray and cryo-EM structures of the mitochondrial calcium uniporter
.
Nature
559
,
575
579
46
Nguyen
,
N.X.
,
Armache
,
J.P.
,
Lee
,
C.
,
Yang
,
Y.
,
Zeng
,
W.
,
Mootha
,
V.K.
et al (
2018
)
Cryo-EM structure of a fungal mitochondrial calcium uniporter
.
Nature
559
,
570
574
47
Yoo
,
J.
,
Wu
,
M.
,
Yin
,
Y.
,
Herzik
, Jr,
M.A.
,
Lander
,
G.C.
and
Lee
,
S.Y.
(
2018
)
Cryo-EM structure of a mitochondrial calcium uniporter
.
Science
361
,
506
511
48
Kamer
,
K.J.
,
Jiang
,
W.
,
Kaushik
,
V.K.
,
Mootha
,
V.K.
and
Grabarek
,
Z.
(
2019
)
Crystal structure of Micu2 and comparison with Micu1 reveal insights into the uniporter gating mechanism
.
Proc. Natl Acad. Sci. U.S.A.
116
,
3546
3555
49
Wu
,
W.
,
Shen
,
Q.
,
Zhang
,
R.
,
Qiu
,
Z.
,
Wang
,
Y.
,
Zheng
,
J.
et al (
2020
)
The structure of the Micu1–Micu2 complex unveils the regulation of the mitochondrial calcium uniporter
.
EMBO J.
39
,
e104285
50
Wang
,
Y.
,
Nguyen
,
N.X.
,
She
,
J.
,
Zeng
,
W.
,
Yang
,
Y.
,
Bai
,
X.C.
et al (
2019
)
Structural mechanism of EMRE-dependent gating of the human mitochondrial calcium uniporter
.
Cell
177
,
1252
1261.e1213
51
Lee
,
Y.
,
Min
,
C.K.
,
Kim
,
T.G.
,
Song
,
H.K.
,
Lim
,
Y.
,
Kim
,
D.
, et al (
2015
)
Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter
.
EMBO Rep.
16
,
1318
1333
52
Van Keuren
,
A.M.
,
Tsai
,
C.W.
,
Balderas
,
E.
,
Rodriguez
,
M.X.
,
Chaudhuri
,
D.
and
Tsai
,
M.F.
(
2020
)
Mechanisms of EMRE-dependent MCU opening in the mitochondrial calcium uniporter complex
.
Cell Rep.
33
,
108486
53
Macewen
,
M.J.
,
Markhard
,
A.L.
,
Bozbeyoglu
,
M.
,
Bradford
,
F.
,
Goldberger
,
O.
,
Mootha
,
V.K.
et al (
2020
)
Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU
.
Life Sci. Alliance
3
,
e202000718
54
Garg
,
V.
,
Suzuki
,
J.
,
Paranjpe
,
I.
,
Unsulangi
,
T.
,
Boyman
,
L.
,
Milescu
,
L.S.
et al (
2021
)
The mechanism of Micu-dependent gating of the mitochondrial Ca2+ uniporter
.
Elife
10
,
e69312
55
Fieni
,
F.
,
Lee
,
S.B.
,
Jan
,
Y.N.
and
Kirichok
,
Y.
(
2012
)
Activity of the mitochondrial calcium uniporter varies greatly between tissues
.
Nat. Commun.
3
,
1317
56
Nemani
,
N.
,
Shanmughapriya
,
S.
and
Madesh
,
M.
(
2018
)
Molecular regulation of MCU: implications in physiology and disease
.
Cell Calcium
74
,
86
93
57
Lambert
,
J.P.
,
Luongo
,
T.S.
,
Tomar
,
D.
,
Jadiya
,
P.
,
Gao
,
E.
,
Zhang
,
X.
et al (
2019
)
Mcub regulates the molecular composition of the mitochondrial calcium uniporter channel to limit mitochondrial calcium overload during stress
.
Circulation
140
,
1720
1733
58
Huo
,
J.
,
Lu
,
S.
,
Kwong
,
J.Q.
,
Bround
,
M.J.
,
Grimes
,
K.M.
,
Sargent
,
M.A.
et al (
2020
)
Mcub induction protects the heart from postischemic remodeling
.
Circ. Res.
127
,
379
390
59
Paillard
,
M.
,
Huang
,
K.T.
,
Weaver
,
D.
,
Lambert
,
J.P.
,
Elrod
,
J.W.
and
Hajnoczky
,
G.
(
2022
)
Altered composition of the mitochondrial Ca2+ uniporter in the failing human heart
.
Cell Calcium
105
,
102618
60
Lombardi
,
A.A.
,
Gibb
,
A.A.
,
Arif
,
E.
,
Kolmetzky
,
D.W.
,
Tomar
,
D.
,
Luongo
,
T.S.
, et al (
2019
)
Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation
.
Nat. Commun.
10
,
4509
61
Tsai
,
C.W.
,
Wu
,
Y.
,
Pao
,
P.C.
,
Phillips
,
C.B.
,
Williams
,
C.
,
Miller
,
C.
et al (
2017
)
Proteolytic control of the mitochondrial calcium uniporter complex
.
Proc. Natl Acad. Sci. U.S.A.
114
,
4388
4393
62
Konig
,
T.
,
Troder
,
S.E.
,
Bakka
,
K.
,
Korwitz
,
A.
,
Richter-Dennerlein
,
R.
,
Lampe
,
P.A.
, et al (
2016
)
The M-Aaa protease associated with neurodegeneration limits MCU activity in mitochondria
.
Mol. Cell
64
,
148
162
63
Ghosh
,
S.
,
Basu Ball
,
W.
,
Madaris
,
T.R.
,
Srikantan
,
S.
,
Madesh
,
M.
,
Mootha
,
V.K.
et al (
2020
)
An essential role for cardiolipin in the stability and function of the mitochondrial calcium uniporter
.
Proc. Natl Acad. Sci. U.S.A.
117
,
16383
16390
64
Balderas
,
E.
,
Eberhardt
,
D.R.
,
Lee
,
S.
,
Pleinis
,
J.M.
,
Sommakia
,
S.
,
Balynas
,
A.M.
, et al (
2022
)
Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during complex I impairment
.
Nat. Commun.
13
,
2769
65
Pan
,
X.
,
Liu
,
J.
,
Nguyen
,
T.
,
Liu
,
C.
,
Sun
,
J.
,
Teng
,
Y.
, et al (
2013
)
The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter
.
Nat. Cell Biol.
15
,
1464
1472
66
Liu
,
J.C.
,
Syder
,
N.C.
,
Ghorashi
,
N.S.
,
Willingham
,
T.B.
,
Parks
,
R.J.
,
Sun
,
J.
, et al (
2020
)
EMRE is essential for mitochondrial calcium uniporter activity in a mouse model
.
JCI Insight
5
,
e134063
67
Alvarez-Illera
,
P.
,
Garcia-Casas
,
P.
,
Fonteriz
,
R.I.
,
Montero
,
M.
and
Alvarez
,
J.
(
2020
)
Mitochondrial Ca2+ dynamics in MCU knockout C. elegans worms
.
Int. J. Mol. Sci.
21
,
8622
68
Murphy
,
E.
,
Pan
,
X.
,
Nguyen
,
T.
,
Liu
,
J.
,
Holmstrom
,
K.M.
and
Finkel
,
T.
(
2014
)
Unresolved questions from the analysis of mice lacking MCU expression
.
Biochem. Biophys. Res. Commun.
449
,
384
385
69
Han
,
Y.
,
Ishibashi
,
S.
,
Iglesias-Gonzalez
,
J.
,
Chen
,
Y.
,
Love
,
N.R.
and
Amaya
,
E.
(
2018
)
Ca2+-induced mitochondrial ROS regulate the early embryonic cell cycle
.
Cell Rep.
22
,
218
231
70
Shanmughapriya
,
S.
,
Tomar
,
D.
,
Dong
,
Z.
,
Slovik
,
K.J.
,
Nemani
,
N.
,
Natarajaseenivasan
,
K.
, et al (
2018
)
Foxd1-dependent Micu1 expression regulates mitochondrial activity and cell differentiation
.
Nat. Commun.
9
,
3449
71
Bulthuis
,
E.P.
,
Adjobo-Hermans
,
M.J.W.
,
De Potter
,
B.
,
Hoogstraten
,
S.
,
Wezendonk
,
L.H.T.
,
Tutakhel
,
O.A.Z.
, et al (
2022
)
Smdt1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement
.
Biorxiv
72
Singh
,
R.
,
Bartok
,
A.
,
Paillard
,
M.
,
Tyburski
,
A.
,
Elliott
,
M.
and
Hajnoczky
,
G.
(
2022
)
Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in micu1-deficient mice and patients
.
Sci. Adv.
8
,
eabj4716
73
Flicker
,
D.
,
Sancak
,
Y.
,
Mick
,
E.
,
Goldberger
,
O.
and
Mootha
,
V.K.
(
2019
)
Exploring the in vivo role of the mitochondrial calcium uniporter in brown fat bioenergetics
.
Cell Rep.
27
,
1364
1375 e1365
74
Xue
,
K.
,
Wu
,
D.
,
Wang
,
Y.
,
Zhao
,
Y.
,
Shen
,
H.
,
Yao
,
J.
et al (
2022
)
The mitochondrial calcium uniporter engages Ucp1 to form a thermoporter that promotes thermogenesis
.
Cell Metab.
34
,
1325
1341.e1326
75
Garbincius
,
J.F.
,
Luongo
,
T.S.
and
Elrod
,
J.W.
(
2020
)
The debate continues: what is the role of MCU and mitochondrial calcium uptake in the heart?
J. Mol. Cell. Cardiol.
143
,
163
174
76
Weinberg
,
S.E.
,
Sena
,
L.A.
and
Chandel
,
N.S.
(
2015
)
Mitochondria in the regulation of innate and adaptive immunity
.
Immunity
42
,
406
417
77
Zheng
,
X.
,
Chen
,
M.
,
Meng
,
X.
,
Chu
,
X.
,
Cai
,
C.
and
Zou
,
F.
(
2017
)
Phosphorylation of dynamin-related protein 1 at Ser616 regulates mitochondrial fission and is involved in mitochondrial calcium uniporter-mediated neutrophil polarization and chemotaxis
.
Mol. Immunol.
87
,
23
32
78
Dong
,
H.
,
Zhao
,
B.
,
Chen
,
J.
,
Liu
,
Z.
,
Li
,
X.
,
Li
,
L.
et al (
2022
)
Mitochondrial calcium uniporter promotes phagocytosis-dependent activation of the Nlrp3 inflammasome
.
Proc. Natl Acad. Sci. U.S.A.
119
,
E2123247119
79
Feno
,
S.
,
Munari
,
F.
,
Reane
,
D.V.
,
Gissi
,
R.
,
Hoang
,
D.H.
,
Castegna
,
A.
et al (
2021
)
The dominant-negative mitochondrial calcium uniporter subunit Mcub drives macrophage polarization during skeletal muscle regeneration
.
Sci. Signal.
14
,
eabf3838
80
Rimessi
,
A.
,
Bezzerri
,
V.
,
Patergnani
,
S.
,
Marchi
,
S.
,
Cabrini
,
G.
and
Pinton
,
P.
(
2015
)
Mitochondrial Ca2+-dependent Nlrp3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis
.
Nat. Commun.
6
,
6201
81
Bisbach
,
C.M.
,
Hutto
,
R.A.
,
Poria
,
D.
,
Cleghorn
,
W.M.
,
Abbas
,
F.
,
Vinberg
,
F.
et al (
2020
)
Mitochondrial calcium uniporter (Mcu) deficiency reveals an alternate path for Ca2+ uptake in photoreceptor mitochondria
.
Sci. Rep.
10
,
16041
82
Hamilton
,
J.
,
Brustovetsky
,
T.
,
Rysted
,
J.E.
,
Lin
,
Z.
,
Usachev
,
Y.M.
and
Brustovetsky
,
N.
(
2018
)
Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria
.
J. Biol. Chem.
293
,
15652
15663
83
Vecellio Reane
,
D.
,
Vallese
,
F.
,
Checchetto
,
V.
,
Acquasaliente
,
L.
,
Butera
,
G.
,
De Filippis
,
V.
et al (
2016
)
A Micu1 splice variant confers high sensitivity to the mitochondrial Ca2+ uptake machinery of skeletal muscle
.
Mol. Cell
64
,
760
773
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