Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses
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ABSTRACT:
PROVIDER: PRJNA1063709 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27497662.fastq.gz | Fastqsanger.gz | |||
| SRR27497663.fastq.gz | Fastqsanger.gz | |||
| SRR27497664.fastq.gz | Fastqsanger.gz | |||
| SRR27497665.fastq.gz | Fastqsanger.gz | |||
| SRR27497666.fastq.gz | Fastqsanger.gz |
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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.
2024-10-23 | GSE253049 | 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:Sustained and balanced Ca2+ increase upon T-cell receptor activation is crucial for regulation of essential T-cell functions including clonal expansion, differentiation and cytokine secretion. Thereby, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. The protein machinery that regulates Ca2+ flux across the inner mitochondrial membrane; the mitochondrial calcium uniporter (MCU) complex, could be thus implicated in T-cell immunity. However, the exact role of mitochondrial Ca2+, and hence, MCU in T-cells is not fully understood. Here, we provide proteomic data of downregulation of MCUa in rat CD4+ T-cells along with control T-cells.
2024-10-23 | PXD048650 | Pride
Project description:Sustained and balanced calcium (Ca2+) increase upon T-cell receptor activation is a fundamental process that regulates essential T-cell functions including proliferation, clonal expansion and cytokine secretion. In this context, mitochondria play an important role and take up Ca2+ to support the elevated bioenergetic demands. Accordingly, alterations in the protein machinery that regulates mitochondrial Ca2+ (mCa2+) flux across the inner mitochondrial membrane; the mitochondrial calcium uniporter (MCU) complex, could be implicated in T-cell immunity. However, the exact role of mCa2+, and thus MCU in T-cells is not fully understood. Here, we show that upon activation of primary human CD4+ T-cells, the MCU complex undergoes a time-dependent compositional rearrangement that causes elevated mCa2+ uptake and increased mitochondrial bioenergetic output. Transcriptome and proteome analyses of naive and effector CD4+ T-cells reveal molecular determinants involved in mitochondrial and T-cell functional reprograming. Moreover, they identify genes, proteins and signaling pathways controlled by mitochondrial Ca2+ homeostasis i.e. the MCU. MCUa knockdown (KD) diminishes mCa2+, 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 (EAE). In summary, our findings imply that mCa2+ uptake through MCU is essential for proper T-cell function and is involved in autoimmunity. Specific MCU inhibitors targeting T-cells could be beneficial for autoimmune suppression and control of immune system dysregulation.
2024-10-24 | PXD048682 | Pride
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: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: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:Mitochondrial Calcium Uniporter Promotes Kidney Aging through Inducing Mitochondrial Calcium-Mediated Renal Tubular Cell Senescence
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Project description:Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The mitochondrial calcium uniporter (MCU) complex is a major route for calcium into the mitochondrial matrix but if and how MCU affects melanoma pathobiology is not understood. Here, we show that MCUA expression correlates with melanoma patient survival, similarly as in kidney, cervical and other cancers, while in pancreatic, breast and liver cancer, this correlation is inverse. Knockdown (KD) of MCUA suppressed melanoma cell growth but promoted migration and invasion in 2D and 3D cultures. In melanoma xenografts, MCUA_KD reduced tumor volumes but promoted lung metastases. Proteomic analyses and protein microarrays identified pathways that link MCUA abundance and melanoma cell phenotype and suggested a major role for metabolic and redox regulation. Accordingly, antioxidants enhanced melanoma cell migration, while pro-oxidants diminished the MCUA_KD-induced invasive phenotype. Furthermore, MCUA_KD amplified the resistance of melanoma cells to immunotherapies and ferroptosis. Col¬lectively, we demonstrate that MCUA controls melanoma aggressive behavior and therapeutic sen¬sitivity. Manipulations of mitochondrial calcium and redox homeostasis, in combination with cur¬rent therapies, should be considered in treating advanced melanoma.
2022-10-30 | PXD029132 | Pride
Project description:Mitochondria regulate bioenergetics, metabolism, and calcium storage, but their role in the placenta and how they may shape offspring metabolic health remains unclear despite associations with pregnancy complications. We examined this relationship by using a murine model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO). We found that female placental trophoblasts exhibited higher respiration rates than males at baseline. MCU deletion impaired mitochondrial function specifically in female placentas, accompanied by changes in metabolomic profiles of amino acid and lipid catabolism. Transcriptome analysis indicated reduced placental cellular growth, which was supported by smaller placentas and reduced embryonic body weights in PI-MCUKO. These deficits normalized postnatally, with body weight and glucose metabolism remaining comparable to the controls under normal chow diet. Notably, under a metabolic challenge of high-fat-diet feeding, Pl-MCUKO females showed reduced weight gain, improved glucose and insulin tolerance, smaller fat depots and increased ambulatory activity, compared to controls. These results provide direct evidence linking placental mitochondrial function to offspring metabolic health.
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