MRNA Expression Changes Induced by Myocardial MCU Inhibition
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE62049 | GEO | 2015/06/07
SECONDARY ACCESSION(S): PRJNA263029
REPOSITORIES: GEO
Similar Datasets
Project description:Mitochondrial calcium is an important second-messenger controlling fight-or-flight responses in the heart. The molecular identity of MCU (Mitochondrial Calcium Uniporter) was recently discovered allowing us to test this hypothesis in vivo by expressing a myocardial delimited dominant negative form of MCU. We queried mRNA expression changes induced by dominant negative MCU expression in the heart. Neonatal (< 24 h) and 6 week old hearts were harvested from mice expressing the dominant negative MCU construct or wild-type littermates.
2015-06-07 | E-GEOD-62049 | biostudies-arrayexpress
Project description:Muscle atrophy contributes to the poor prognosis of many physiopathological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca2+] which control aerobic metabolism, cell death and survival pathways. We have investigated in vivo the effects of mitochondrial Ca2+ homeostasis in skeletal muscle function and trophism, by overexpressing or silencing the Mitochondrial Calcium Uniporter (MCU). The results coherently demonstrate that both in developing and in adult muscles MCU-dependent mitochondrial Ca2+ uptake has a marked trophic effect that does not depend on autophagy or aerobic control, but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1M-NM-14 and Igf1-Akt/PKB. In adult mice, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca2+-dependent organelle-to-nucleus signaling route, which links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in sarcopenia. Experiments were performed on biological replicates of single skeletal muscle fibres. Seven fibres were chosen for their Mutochondrial Calcium Uniporter (MCU) overexpression and other seven fibres because MCU was silenced. Overexpression and silencing were performed injecting skeletal muscle with AAV containing MCU gene or short interfering oligos specific for MCU. As control was profiled eigth fibres transfected with AAV and eigth wild type fibres. Analyses were performed 7 days and 14 days after the AAV injection (3 fibers after 7 days and 4 fibers after 14 days for MCU overexpression and silencing, four fibres after 7 days and four after 14 days for control).
2015-03-05 | E-GEOD-60931 | biostudies-arrayexpress
Project description:Rhabdomyosarcoma (RMS), the most common paediatric soft-tissue sarcoma, is characterized by cells of skeletal muscle origin that fail to both irreversibly exit the cell cycle and complete skeletal muscle differentiation. Embryonal rhabdomyosarcoma (ERMS) is the most prevalent subtype of RMS and its molecular signatures has been associated with metabolism defects and increased oxidative stress. However, the details of the contributing factors or molecules have not been studied. Both metabolism and oxidative stress are associated with mitochondrial functions and an important molecule that regulates mitochondrial functions is calcium. Till date, there has been no studies that examine the role of mitochondrial calcium in ERMS. In addition, the molecular component of mitochondrial calcium uniporter complex, which is responsible for the uptake of mitochondrial calcium was only discovered in 2012. Since then, there has been an increasing interest in investigating the role of mitochondrial calcium and mitochondrial calcium uniporter complex in various cancers. Mitochondrial calcium uniporter (MCU), the main channel forming protein is often found to be dysregulated in various cancers. Our preliminary data has shown that mitochondrial calcium is dysregulated in ERMS due to overexpression of MCU. This dysregulation of mitochondrial calcium has led to multiple mitochondrial dysfunctions and oncogenic phenotypes. Hence, we would like to investigate the downstream targets of MCU in order to identify the mechanism through which MCU regulates oncogenic phenotypes in ERMS.
2022-05-04 | GSE173200 | GEO
Project description:Cardiomyocyte Ca2+ is buffered by mitochondria via the mitochondrial calcium uniporter (MCU) complex. The MCU complex consists of pore-forming proteins including the mitochondrial calcium uniporter (MCU), and regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 affected the expression of MCU-associated genes. To further explore this, we knocked down Tug1 (Tug1 KD) in H9c2 rat cardiomyocytes using antisense LNA oligo. This led to increased MCU protein expression yet this did not enhance a marker of mitochondrial Ca2+ uptake. RNA-seq revealed that Tug1 KD increased Mcu and led to differential expression of genes and pathways related to Ca2+ regulation in the heart. To understand the effect of this on Ca2+ signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to promote Mcu gene expression. Tug1 KD attenuated the increase in CAMKII and CREB phosphorylation in response to ionomycin, a Ca2+ ionophore. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD mediated increase in Mcu. Together, these data suggest that Tug1 modulates MCU expression via a mechanism that may involve CAMKII and CREB. The Tug1 mediated regulation of MCU on mitochondrial Ca2+ uptake, may have functional consequences for cellular Ca2+ handling which could have implications for cardiac disease.
2023-07-22 | GSE237787 | GEO
Project description:Mitochondrial calcium regulates bioenergetics but also serves as a trigger for cell death.1 With a sustained increase in catecholamine or a large increase in cytosolic calcium as occurs with ischemia, mitochondrial calcium can rise to high levels, leading to activation of the mitochondrial permeability transition pore, thus initiating cell death.1 Calcium uptake into mitochondria occurs via the MCU (mitochondrial calcium uniporter), which is regulated by 3 EF (EF hand protein) hand proteins, MICU (mitochondrial calcium uptake) 1, 2, and 3.2 MICU1/MCU ratios vary in different tissues,3 and alterations in substrate flux have been shown to regulate MICU1 levels altering MCU-mediated calcium uptake.4 MICU3 has generally been thought to function primarily in neuronal tissue where it is highly expressed and thus has been largely ignored in other tissues such as the heart. We performed quantitative proteomics using Tandem mass tag labeling coupled to liquid chromatography and tandem mass spectrometry to analyze MCU and MCU regulators in cardiac and hepatic mitochondria (Figure [A]). Normalizing MICU levels to MCU in heart and liver mitochondria, we found that the MICU1/MCU ratio was 0.75 in liver and 0.25 in heart, which is consistent with previous studies3; however, the MICU3/MCU ratio in heart is >3-fold higher than that found in liver. To confirm that the MICU3 we observed in heart mitochondria was not due to contamination by mitochondria from nerve tissue in heart, we isolated cardiomyocytes and compared the ratio of MICU3 to MCU in cardiomyocytes and heart mitochondria and found similar ratios (Figure [B]). These data suggest that MICU3 might play a role in regulating MCU in heart.
2021-11-23 | MSV000088439 | MassIVE
Project description:The mitochondrial calcium uniporter has been proposed to coordinate the organelle’s energetics with cytosolic calcium signaling. Previous studies have shown that the uniporter current is extremely high in mitochondria from brown adipose tissue (BAT), yet the contribution of the uniporter to BAT physiology in vivo is not known. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice are born in Mendelian ratios on a C57BL6/J genetic background, without any overt phenotypes. Although uniporter based calcium uptake is selectively ablated in BAT mitochondria, these mice are able to defend their body temperature in response to cold challenge and exhibit a normal body weight trajectory on a high fat diet. BAT transcriptional profiles at baseline and following cold-challenge are intact and not impacted by loss of Mcu. Unexpectedly, we found that cold powerfully activates the ATF4-dependent integrated stress response in BAT, and increases both circulating FGF21 and GDF15 levels, raising the hypothesis that the integrated stress response partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis, and unexpectedly, uncovers a striking activation of the integrated stress response of BAT to cold challenge.
2019-04-30 | GSE119964 | GEO
Project description:Muscle atrophy contributes to the poor prognosis of many physiopathological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca2+] which control aerobic metabolism, cell death and survival pathways. We have investigated in vivo the effects of mitochondrial Ca2+ homeostasis in skeletal muscle function and trophism, by overexpressing or silencing the Mitochondrial Calcium Uniporter (MCU). The results coherently demonstrate that both in developing and in adult muscles MCU-dependent mitochondrial Ca2+ uptake has a marked trophic effect that does not depend on autophagy or aerobic control, but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1α4 and Igf1-Akt/PKB. In adult mice, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca2+-dependent organelle-to-nucleus signaling route, which links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in sarcopenia.
2015-03-05 | GSE60931 | GEO
Project description:Influx of Ca2+ across the inner mitochondrial membrane via the mitochondrial Ca2+ uniporter (MCU) enhances the activity of several electron transport chain dehydrogenases and the F1F0 ATP synthase. In this study, we investigated the role of MCUb, an MCU complex gene product that is a direct inhibitor of MCU mediated Ca2+ influx. We find MCUb expression to be induced by caloric restriction in heart, skeletal muscle, liver and kidney where it functions as a metabolic activator of mitochondrial fatty acid utilization. Mice selectively deficient for Mcub in skeletal muscle showed a metabolic signature of deficient fatty acid utilization in muscle, associated with progressive age-related obesity, glucose intolerance and metabolic syndrome. To define transcriptional changes underlying, and potentially contributing to this regulation of Ca2+-dependent mitochondrial fatty acid utilization, microarray analyses of tibialis anterior (TA) muscle from control and knockout mice was carried out. We used microarrays to elucidate effects of MCU and MCUb ablation on transcriptional profiles of TA muscle
2023-11-07 | GSE205193 | GEO
Project description:To explore the role of the mitochondrial Ca2+ uniporter (MCU) in exosomal microRNA(miRNA) sorting in MDA-MB-231 cells, we isolated miRNA from the exosomes derived from MCU-downregulated and control MDA-MB-231 cells. We then performed Next Generation Sequencing (NGS) and real-time quantitative polymerase chain reaction (qRT-PCR) to find and validate differetial expressed exosomal miRNAs that regulated by MCU.
2021-04-19 | GSE113411 | GEO
Project description:Chronic low-grade inflammation is a hallmark of aging, but its etiology is not well understood. Mitochondrial dysfunction has been linked to both cellular senescence and age-related inflammation or inflammaging but fundamental mechanisms underlying these links are unclear. We analyzed age-related gene expression in different human tissues and discovered that in blood, the mRNA expression of Mitochondrial Calcium Uniporter (MCU) and its regulatory subunit MICU1 correlated inversely with age. MCU is the pore-forming subunit of a Ca2+-selective ion channel complex residing in the mitochondrial inner membrane and is the main conduit for Ca2+-influx into the mitochondrial matrix. Based on these findings we tested the simple hypothesis that mitochondrial Ca2+ uptake capacity of macrophages decreases with age. We found a significant reduction in the mitochondrial Ca2+-uptake capacity of macrophages derived from aged (80-90 weeks) mice. Notably, these macrophages display amplified cytosolic Ca2+ elevations and increased inflammatory output. To test the salience of mitochondrial calcium uptake in regulating macrophage inflammatory output, we deleted Mcu selectively in macrophages. The Mcu-/- macrophages of young mice (<25 weeks) express more inflammatory genes at baseline and show a hyper-inflammatory response when stimulated. We show that reduced mitochondrial Ca2+ amplifies cytosolic Ca2+ oscillations and potentiates downstream NFkB activation, which is central to inflammation. The regulation of inflammatory response by mitochondrial Ca2+ uptake is also seen readily in human macrophages. The siRNA-mediated knockdown of MCU in human blood derived macrophages recapitulates the phenomenon – the mitochondrial Ca2+-uptake is greatly reduced, cytosolic Ca2+ elevations are more pronounced, and the macrophages are hyper-inflammatory. Our findings pinpoint the MCU complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation. Resident macrophages are intrinsic to every organ system and the steady erosion of their mitochondrial Ca2+-uptake capacity may play a germinal or exacerbating role in many age-related neurodegenerative, cardiometabolic, renal and musculoskeletal diseases that afflict us.
2023-04-19 | GSE228873 | GEO