Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses
Magdalena Shumanska, Dmitri Lodygin, Christine S. Gibhardt, Christian Ickes, Ioana Stejerean‐Todoran, Lena C.M. Krause, Kira Pahl, Lianne H.C. Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J. Legler, Martin Haubrock, Mišo Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski
Abstract
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 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.