Mitochondrial Calcium Uniporter Promotes Kidney Aging through Inducing Mitochondrial Calcium-Mediated Renal Tubular Cell Senescence
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ABSTRACT:
PROVIDER: PRJNA1092075 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28464371_1.fastq.gz | Fastqsanger.gz | |||
| SRR28464371_2.fastq.gz | Fastqsanger.gz | |||
| SRR28464372_1.fastq.gz | Fastqsanger.gz | |||
| SRR28464372_2.fastq.gz | Fastqsanger.gz | |||
| SRR28464373_1.fastq.gz | Fastqsanger.gz |
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Project description:Kidney is a vital organ responsible for homeostasis in the body. To retard kidney aging is of great importance for maintaining body health. Whereas the therapeutic strategies targeting against kidney aging are not elucidated. Recent studies show mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, however, the underlying mechanisms of mitochondrial dysfunction in kidney aging have not been demonstrated. Herein, we found calcium overload, and the mitochondrial calcium uniporter (MCU) was induced in renal tubular cells and aged kidney. To activate MCU not only triggered mitochondrial calcium overload, but also induced reactive oxygen species (ROS) production and cellular senescence and age-related kidney fibrosis. Inversely, to block MCU or chelate calcium diminished ROS generation, restored mitochondrial homeostasis, and retarded cell senescence and protected against kidney aging. These results demonstrate MCU plays a key role in promote renal tubular cell senescence, which provides a new insight on the therapeutic strategy for fighting against kidney aging.
2024-10-02 | GSE262514 | 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-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: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.
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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.
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Project description:Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses
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Project description:Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways, and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss- and gain-of-function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism, and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes, and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism in FLC.
2025-04-11 | GSE291658 | GEO
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.
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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.
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Project description:T-cell receptor-induced Ca2+ signals are essential for proper T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. The protein machinery that regulates mitochondrial Ca2+ (mCa2+) uptake; the mitochondrial calcium uniporter (MCU) complex, could be thus implicated in T-cell immunity. However, the exact role of MCU in T-cells is not understood. Here, we show that upon activation of naïve T-cells, the MCU complex undergoes a compositional rearrangement that causes elevated mCa2+ uptake and increased bioenergetic output. Transcriptome and proteome analyses reveal molecular determinants involved in mitochondrial functional reprograming and identify signaling pathways controlled by MCU. MCUa knockdown diminishes mCa2+ uptake, mitochondrial respiration and ATP production as well as T-cell invasion and cytokine secretion. In vivo, downregulation of MCUa in rat CD4+ T-cells suppresses autoimmune responses in a multiple sclerosis model of inflammatory experimental autoimmune encephalomyelitis. In summary, Ca2+ uptake through MCU is essential for proper T-cell function and is involved in autoimmunity. T-cell specific MCU inhibition is a potential tool for treating autoimmune disorders.
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