The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

Patrón, Maria; Raffaello, Anna; Granatiero, Veronica; Tosatto, Anna; Merli, Giulia; Stefani, Diego De; Wright, Lauren E.; Pallafacchina, Giorgia; Terrin, Anna; Mammucari, Cristina; Meneghesso, Gaudenzio

doi:10.1074/jbc.r112.420752

Cited by 152 publications

(110 citation statements)

References 87 publications

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“…Ca 2+ uptake from the mitochondrial intermembrane space into the mitochondrial matrix occurs predominantly through the MCU complex containing the Ca 2+ selective ion channel MCU (Mitochondrial Calcium Uniporter) [49,50] and several accessory proteins [51][52][53][54]. Recalling that OPA1 knockdown increases the diffusibility of cytochrome c through the crista junctions [38,45,46] we postulated that if significant Ca 2+ uptake into the matrix occurs from the lumen of the cristae, reduced expression of Opa1 would increase the access of Ca 2+ to the transporters in the crista membrane and consequently would enhance Ca 2+ uptake.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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The most frequent form of hereditary blindness, Autosomal Dominant Optic Atrophy (ADOA) is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca 2+ uptake (Fülöp et al.,PLoS One 2011). Therefore we studied mitochondrial Ca 2+ metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell -inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca 2+ signals. The present data indicate that enhanced mitochondrial Ca 2+ uptake is a pathogenetic factor in the progress of ADOA.3

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Fülöp¹,

Rajki²,

Maka³

et al. 2015

Cell Calcium

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“…P < 0.05 (Student's t test). n ¼ 4-6 decrease in membrane potential, and consequently loss of mitochondrial functions and cell death (Patron et al 2013). Ca 2+ fluctuations may interfere in lysosomal homeostasis, which interfere in a variety of mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology

et al. 2017

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Mucopolysaccharidosis type I (MPS I), a rare autosomal recessive disease, is caused by a deficiency of the lysosomal enzyme alfa-L-iduronidase. Impaired enzyme activity promotes glycosaminoglycans accumulation in several tissues and organs, leading to complex multisystemic complications. Several studies using animal models indicated different intracellular pathways involving MPS I physiopathology; however, the exact mechanisms underlying this syndrome are still not understood. Previous results from our group showed alterations in ionic homeostasis and cell viability of splenocytes and macrophages in IduaÀ/À mice. In the present study, we found altered intracellular ionic homeostasis in a different cell type (fibroblasts) from the same murine model. IduaÀ/À fibroblasts from 3-month-old mice presented higher cytoplasmatic and endoplasmic reticulum Ca 2+ concentration, lower levels of mitochondrial Ca 2+ and mitochondrial membrane potential and higher cytoplasmatic pH when compared to Idua+/+ animals. Also, IduaÀ/À fibroblasts were more resistant to the apoptotic induction with staurosporine, indicating a possible resistance to apoptotic induction in those cells. In addition, despite the intracellular ionic imbalance, no significant alterations were found in apoptosis and autophagy in IduaÀ/À fibroblasts, which implies that the ionic alterations did not activate those pathways. The investigation of mechanisms underlying the cellular physiopathology of lysosomal diseases is crucial for a better understanding about the progression of these diseases. Since splenocytes, macrophages, and fibroblasts have different embryonic origins and distinct structural and functional features, potentially altered signaling pathways found in a cell-specific manner in an alfa-L-iduronidasedeficient environment provide additional understanding of the clinical multisystemic presentation of this disease and provide new basis for improved therapeutic approaches.

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“…In somatic cells, mitochondrial calcium uptake is undertaken by a mitochondrial calcium uniporter (MCU; Fig. 2) and is known to control intracellular calcium signals, cell metabolism and cell survival (for recent reviews, see Rizzuto et al (2012) and Patron et al (2013)). Proteomic data have confirmed that human sperm do possess MCU, as well as MCU regulator 1 , Wang et al 2013.…”

Section: C Signallingmentioning

confidence: 99%

Mitochondria functionality and sperm quality

Amaral¹,

Lourenço²,

Marques³

et al. 2013

Reproduction

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Although mitochondria are best known for being the eukaryotic cell powerhouses, these organelles participate in various cellular functions besides ATP production, such as calcium homoeostasis, generation of reactive oxygen species (ROS), the intrinsic apoptotic pathway and steroid hormone biosynthesis. The aim of this review was to discuss the putative roles of mitochondria in mammalian sperm function and how they may relate to sperm quality and fertilisation ability, particularly in humans. Although paternal mitochondria are degraded inside the zygote, sperm mitochondrial functionality seems to be critical for fertilisation. Indeed, changes in mitochondrial integrity/functionality, namely defects in mitochondrial ultrastructure or in the mitochondrial genome, transcriptome or proteome, as well as low mitochondrial membrane potential or altered oxygen consumption, have been correlated with loss of sperm function (particularly with decreased motility). Results from genetically engineered mouse models also confirmed this trend. On the other hand, increasing evidence suggests that mitochondria derived ATP is not crucial for sperm motility and that glycolysis may be the main ATP supplier for this particular aspect of sperm function. However, there are contradictory data in the literature regarding sperm bioenergetics. The relevance of sperm mitochondria may thus be associated with their role in other physiological features, particularly with the production of ROS, which in controlled levels are needed for proper sperm function. Sperm mitochondria may also serve as intracellular Ca 2C stores, although their role in signalling is still unclear.

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The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

Cited by 152 publications

References 87 publications

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology

Mitochondria functionality and sperm quality

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