Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.

Autor: Shumanska M; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Lodygin D; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre, Georg-August-University, Göttingen, Germany., Gibhardt CS; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Ickes C; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Stejerean-Todoran I; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Krause LCM; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Pahl K; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Jacobs LJHC; Redox Metabolism, Institute of Biochemistry and CECAD, University of Cologne, Cologne, Germany., Paluschkiwitz A; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Liu S; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany., Boshnakovska A; Department of Cellular Biochemistry, University Medical Centre, Georg-August-University, Göttingen, Germany., Voigt N; Institute of Pharmacology and Toxicology, University Medical Centre, Georg-August-University, Göttingen, Germany., Legler TJ; Department of Transfusion Medicine, University Medical Centre, Göttingen, Germany., Haubrock M; Department of Medical Bioinformatics, University Medical Centre, Georg-August-University, Göttingen, Germany., Mitkovski M; City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany., Poschmann G; Institute for Molecular Medicine, Proteome Research, University Hospital and Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Rehling P; Department of Cellular Biochemistry, University Medical Centre, Georg-August-University, Göttingen, Germany., Dennerlein S; Department of Cellular Biochemistry, University Medical Centre, Georg-August-University, Göttingen, Germany., Riemer J; Redox Metabolism, Institute of Biochemistry and CECAD, University of Cologne, Cologne, Germany., Flügel A; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Centre, Georg-August-University, Göttingen, Germany., Bogeski I; Molecular Physiology, Institute of Cardiovascular Physiology, University Medical Centre, Georg-August-University, Göttingen, Germany. ivan.bogeski@med.uni-goettingen.de.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2024 Dec 02. Date of Electronic Publication: 2024 Dec 02.
DOI: 10.1038/s44319-024-00313-4
Abstrakt: T-cell receptor (TCR)-induced Ca 2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca 2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca 2+ -uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca 2+ ( m Ca 2+ ) uptake in primary naive and effector human CD4 + T-cells. Compared to naive T-cells, effector T-cells display elevated m Ca 2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUa KD ), diminishes m Ca 2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUa KD in rat CD4 + T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that m Ca 2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.
Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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