A MICU1 Splice Variant Confers High Sensitivity to the Mitochondrial Ca2+ Uptake Machinery of Skeletal Muscle

Reane, Denis Vecellio; Vallese, Francesca; Checchetto, Vanessa; Acquasaliente, Laura; Butera, Gaia; Filippis, Vincenzo De; Szabó, Ildikò; Zanotti, Giuseppe; Meneghesso, Gaudenzio; Raffaello, Anna

doi:10.1016/j.molcel.2016.10.001

Cited by 98 publications

(107 citation statements)

References 31 publications

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“…The prevalence of mitochondrial Ca 2+ overload in skeletal muscle disorders may reflect the larger magnitude of uniporter-mediated transport. Uniporter current density in skeletal muscle is 30 times larger than in heart[36], and becomes active at lower cytoplasmic Ca 2+ levels[51]. Thus, given the already-large flux, skeletal muscle mitochondria may be far more prone to pathological Ca 2+ overload, and not achieve any benefit by enhancing the flux further.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Sommakia

Houlihan

Deane

et al. 2017

Journal of Molecular and Cellular Cardiology

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Calcium (Ca2+) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca2+ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca2+ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes. By the second postnatal week (10–15 day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca2+ during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca2+ uniporter, the main portal for Ca2+ entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na+-Ca2+) exchanger, the main portal for Ca2+ efflux, is inhibited. These changes in activity reflect changes in protein expression of the corresponding transporter subunits. While decreased transcription of Nclx, the gene encoding the Na+-Ca2+ exchanger, explains diminished Na+-Ca2+ exchange, the mechanism for enhanced uniporter expression appears to be post-transcriptional. Notably, such changes allow cardiac mitochondria from Tfam knockout animals to be far more sensitive to Ca2+-induced increases in respiration. In the absence of Ca2+, oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca2+. Thus, we demonstrate a phenotype of enhanced mitochondrial Ca2+ in a mitochondrial cardiomyopathy model, and show that such Ca2+ accumulation is capable of rescuing deficits in energy synthesis capacity in vitro.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Sommakia

Houlihan

Deane

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…Nonetheless, the affinity for Ca 2+ of the EF-hand domains is still controversial. As for MICU1, K d measurements performed by isothermal titration calorimetry range from 4 to 40 μM [111, 115], while measurements of intrinsic tryptophan fluorescence record a higher affinity, with a K d of ~ 300 nM [47]. These discrepancies, reflecting the different technical approaches, surely need further investigation.…”

Section: The Molecular Characterization Of the Mcu Complexmentioning

confidence: 99%

“…On the other hand, MICU1 senses high [Ca 2+ ] and it allows the cooperative activation of MCU during cytosolic Ca 2+ increases. Along these lines, MICU1 silencing causes Ca 2+ overload due to the loss of the gatekeeper MICU2 and reduces the maximal activation of MCU due to the loss of cooperativity [27, 47, 77, 83, 111]. Nonetheless, the stoichiometry of MCU regulators in the complex is still completely unknown.…”

Section: The Molecular Characterization Of the Mcu Complexmentioning

confidence: 99%

“…It is thus not surprising that, compared to other tissues, skeletal muscle mitochondria display high Ca 2+ conductance [29] and that skeletal muscle expresses a unique MCU Ca 2+ uptake machinery [111]. Indeed, recently, an alternative splice variant of MICU1, that was named MICU1.1, was discovered [111]. This isoform, characterized by the addition of a micro-exon coding for four amino acids, greatly modifies the properties of the MCU.…”

Section: Mitochondrial Ca2+ Signaling In Physiology: General Framewormentioning

confidence: 99%

“…In detail, MICU1.1 binds Ca 2+ one order of magnitude more efficiently than MICU1 and, when heterodimerized with MICU2, activates MCU current at lower Ca 2+ concentrations than MICU1-MICU2 heterodimers. In vivo injection of antisense oligonucleotides mediating exon skipping of the MICU1.1 extra exon, and thus forced expression of MICU1, demonstrated that MICU1.1 is required for maintaining sufficient levels of mitochondrial Ca 2+ uptake to provide the ATP needed for contraction [111] (Fig. 5).…”

Section: Mitochondrial Ca2+ Signaling In Physiology: General Framewormentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

Mammucari

Raffaello

Reane

et al. 2018

Pflugers Arch - Eur J Physiol

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138

125

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Mitochondrial Ca2+ is involved in heterogeneous functions, ranging from the control of metabolism and ATP production to the regulation of cell death. In addition, mitochondrial Ca2+ uptake contributes to cytosolic [Ca2+] shaping thus impinging on specific Ca2+-dependent events. Mitochondrial Ca2+ concentration is controlled by influx and efflux pathways: the former controlled by the activity of the mitochondrial Ca2+ uniporter (MCU), the latter by the Na+/Ca2+ exchanger (NCLX) and the H+/Ca2+ (mHCX) exchanger. The molecular identities of MCU and of NCLX have been recently unraveled, thus allowing genetic studies on their physiopathological relevance. After a general framework on the significance of mitochondrial Ca2+ uptake, this review discusses the structure of the MCU complex and the regulation of its activity, the importance of mitochondrial Ca2+ signaling in different physiological settings, and the consequences of MCU modulation on organ physiology.

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Microexon alternative splicing of small GTPase regulators: Implication in central nervous system diseases

2021

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Microexons are small sized (≤51 bp) exons which undergo extensive alternative splicing in neurons, microglia, embryonic stem cells, and cancer cells, giving rise to cell type specific protein isoforms. Due to their small sizes, microexons provide a unique challenge for the splicing machinery. They frequently lack exon splicer enhancers/repressors and require specialized neighboring trans-regulatory and cis-regulatory elements bound by RNA binding proteins (RBPs) for their inclusion. The functional consequences of including microexons within mRNAs have been extensively documented in the central nervous system (CNS) and aberrations in their inclusion have been observed to lead to abnormal processes. Despite the increasing evidence for microexons impacting cellular physiology within CNS, mechanistic details illustrating their functional importance in diseases of the CNS is still limited. In this review, we discuss the unique characteristics of microexons, and how RBPs participate in regulating their inclusion and exclusion during splicing. We consider recent findings of microexon alternative splicing and their implication for regulating the function of small GTPases in the context of the microglia, and we extrapolate these findings to what is known in neurons. We further discuss the emerging evidence for dysregulation of the Rho GTPase pathway in CNS diseases and the consequences contributed by the mis-splicing of microexons.

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A MICU1 Splice Variant Confers High Sensitivity to the Mitochondrial Ca2+ Uptake Machinery of Skeletal Muscle

Cited by 98 publications

References 31 publications

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

Microexon alternative splicing of small GTPase regulators: Implication in central nervous system diseases

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