Expression of mRNA Encoding Mcu and Other Mitochondrial Calcium Regulatory Genes Depends on Cell Type, Neuronal Subtype, and Ca2+ Signaling

Márkus, Nóra M.; Hasel, Philip; Qiu, Jing; Bell, Karen; Heron, Samuel; Kind, Peter C.; Dando, Owen; Simpson, T. Ian; Hardingham, Giles E.

doi:10.1371/journal.pone.0148164

Cited by 30 publications

(31 citation statements)

References 67 publications

(74 reference statements)

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“…The only noticeable difference compared to the other members of the MICU family is the presence of an additional domain (50 amino acids) in the central part of the protein (Figure 1A). As to its expression, we confirmed by real time PCR that also in mice MICU3 is expressed at high levels in the brain (Figure 1B), as already reported20,36.…”

Section: Resultssupporting

confidence: 86%

“…Indeed, on one hand MCUb, the endogenous dominant negative MCU isoform17, is mainly expressed in adipose tissue, blood and spleen. On the other hand, MICU3 is expressed at high levels in the central nervous system (CNS), in line with previous reports20,36. We thus looked in greater detail at MICU3 as an uncharacterized MCU regulator mainly expressed in the nervous system.…”

Section: Resultssupporting

confidence: 63%

“…Previous data20,36 and real time PCR on mouse tissues (Figure 1B) confirmed that MICU3 is mainly a brain-specific MCU complex component, although recent work showed low but detectable MICU3 protein also in skeletal muscle44. The other members of the MICU family are known to be the key regulators of MCU gating27–31,37.…”

Section: Discussionmentioning

confidence: 54%

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MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

et al. 2018

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The versatility and universality of Ca2+ as intracellular messenger is guaranteed by the compartmentalization of changes in [Ca2+]. In this context, mitochondrial Ca2+ plays a central role, by regulating both specific organelle functions and global cellular events. This versatility is also guaranteed by a cell type-specific Ca2+ signaling toolkit controlling specific cellular functions. Accordingly, mitochondrial Ca2+ uptake is mediated by a multimolecular structure, the MCU complex, which differs among various tissues. Its activity is indeed controlled by different components that cooperate to modulate specific channeling properties. We here investigate the role of MICU3, an EF-hand containing protein expressed at high levels especially in brain. We show that MICU3 forms a disulfide bond-mediated dimer with MICU1, but not with MICU2, and it acts as enhancer of MCU-dependent mitochondrial Ca2+ uptake. Silencing of MICU3 in primary cortical neurons impairs Ca2+ signals elicited by synaptic activity, thus suggesting a specific role in regulating neuronal function.

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Section: Resultssupporting

confidence: 86%

Section: Resultssupporting

confidence: 63%

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MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

et al. 2018

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“…3E). A similar regulation of mitochondrial calcium handling has been observed in other excitable tissues (48,(73)(74)(75) either by tissue-specific expression of Mcu components (Micu1-3) or by posttranslational modification (e.g. redox state) (76).…”

Section: Discussionsupporting

confidence: 65%

Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

Fecher

Trovò

Müller

et al. 2018

Preprint

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Mitochondria vary in morphology and function in different tissues, however little is known about their molecular diversity among cell types. To investigate mitochondrial diversity in vivo, we developed an efficient protocol to isolate cell type-specific mitochondria based on a new MitoTag mouse. We profiled the mitochondrial proteome of three major neural cell types in cerebellum and identified a substantial number of differential mitochondrial markers for these cell types in mice and humans. Based on predictions from these proteomes, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neurons. Moreover, we identified Rmdn3 as a major determinant of ER-mitochondria proximity in Purkinje cells. Our novel approach enables exploring mitochondrial diversity on the functional and molecular level in many in vivo contexts.

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“…Indeed, cytosolic calcium appears to play essential roles in cell survival and physiology [30,31,32,33]. However, although intracellular receptors are key players in the dynamics of cytosolic calcium [34,35], there are very few studies related to deprivation of oxygen and intracellular calcium channels [36,37,38,39].…”

Section: Discussionmentioning

confidence: 99%

Functional Role of Intracellular Calcium Receptor Inositol 1,4,5-Trisphosphate Type 1 in Rat Hippocampus after Neonatal Anoxia

et al. 2017

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Anoxia is one of the most prevalent causes of neonatal morbidity and mortality, especially in preterm neonates, constituting an important public health problem due to permanent neurological sequelae observed in patients. Oxygen deprivation triggers a series of simultaneous cascades, culminating in cell death mainly located in more vulnerable metabolic brain regions, such as the hippocampus. In the process of cell death by oxygen deprivation, cytosolic calcium plays crucial roles. Intracellular inositol 1,4,5-trisphosphate receptors (IP3Rs) are important regulators of cytosolic calcium levels, although the role of these receptors in neonatal anoxia is completely unknown. This study focused on the functional role of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in rat hippocampus after neonatal anoxia. Quantitative real-time PCR revealed a decrease of IP3R1 gene expression 24 hours after neonatal anoxia. We detected that IP3R1 accumulates specially in CA1, and this spatial pattern did not change after neonatal anoxia. Interestingly, we observed that anoxia triggers translocation of IP3R1 to nucleus in hippocampal cells. We were able to observe that anoxia changes distribution of IP3R1 immunofluorescence signals, as revealed by cluster size analysis. We next examined the role of IP3R1 in the neuronal cell loss triggered by neonatal anoxia. Intrahippocampal injection of non-specific IP3R1 blocker 2-APB clearly reduced the number of Fluoro-Jade C and Tunel positive cells, revealing that activation of IP3R1 increases cell death after neonatal anoxia. Finally, we aimed to disclose mechanistics of IP3R1 in cell death. We were able to determine that blockade of IP3R1 did not reduced the distribution and pixel density of activated caspase 3-positive cells, indicating that the participation of IP3R1 in neuronal cell loss is not related to classical caspase-mediated apoptosis. In summary, this study may contribute to new perspectives in the investigation of neurodegenerative mechanisms triggered by oxygen deprivation.

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Expression of mRNA Encoding Mcu and Other Mitochondrial Calcium Regulatory Genes Depends on Cell Type, Neuronal Subtype, and Ca2+ Signaling

Cited by 30 publications

References 67 publications

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

Functional Role of Intracellular Calcium Receptor Inositol 1,4,5-Trisphosphate Type 1 in Rat Hippocampus after Neonatal Anoxia

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