Abstract (Expand)
Abstract
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 …xt, 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.
Authors: Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski
Date Published: 2nd Dec 2024
Publication Type: Journal Article
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