Abstract
T cell activation and differentiation is associated with metabolic reprogramming to cope with the increased bioenergetic demand and to provide metabolic intermediates for the biosynthesis of building blocks. Antigen receptor stimulation not only promotes the metabolic switch of lymphocytes but also triggers the uptake of calcium (Ca2+) from the cytosol into the mitochondrial matrix. Whether mitochondrial Ca2+ influx through the mitochondrial Ca2+ uniporter (MCU) controls T cell metabolism and effector function remained, however, enigmatic. Using mice with T cell-specific deletion of MCU, we here show that genetic inactivation of mitochondrial Ca2+ uptake increased cytosolic Ca2+ levels following antigen receptor stimulation and store-operated Ca2+ entry (SOCE). However, ablation of MCU and the elevation of cytosolic Ca2+ did not affect mitochondrial respiration, differentiation and effector function of inflammatory and regulatory T cell subsets in vitro and in animal models of T cell-mediated autoimmunity and viral infection. These data suggest that MCU-mediated mitochondrial Ca2+ uptake is largely dispensable for murine T cell function. Our study has also important technical implications. Previous studies relied mostly on pharmacological inhibition or transient knockdown of mitochondrial Ca2+ uptake, but our results using mice with genetic deletion of MCU did not recapitulate these findings. The discrepancy of our study to previous reports hint at compensatory mechanisms in MCU-deficient mice and/or off-target effects of current MCU inhibitors.
Highlights
Mitochondria play a pivotal role in cellular metabolism by producing large amounts of ATP through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO)
Our best explanation why we did not measure significant mitochondrial Ca2+ uptake in these experiments is that primary T cells have fewer and relatively small mitochondria compared to other immune cells, such as macrophages, which makes it difficult to monitor their Ca2+ buffering capacity
In stressed or chronically activated cells, mitochondrial Ca2+ uniporter (MCU) triggers mitochondrial Ca2+ overload that causes the opening of the mPTP and the release of pro-apoptotic factors
Summary
Mitochondria play a pivotal role in cellular metabolism by producing large amounts of ATP through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Intermediates of mitochondrial metabolism, such as tricarboxylic acid (TCA) cycle, glutaminolysis and FAO, control the fate and function of immune cells by regulating signaling pathways, the cellular redox balance, apoptosis and epigenetic rewiring through DNA and histone modifications. Studies in myocytes and other nonimmune cells demonstrated that mitochondrial Ca2+ handling can regulate mitochondrial metabolism and function, including the activity of the TCA cycle and the electron transport chain (ETC), the production of reactive oxygen species (ROS) and apoptosis through opening of the mitochondrial permeability transition pore (mPTP) (Finkel et al, 2015; Wang P. et al, 2020). Essential MCU regulator (EMRE) and its homologue MCUb were shown to be part of the channel pore, whereas the two EF hand domaincontaining proteins mitochondrial Ca2+ uptake 1 (MICU1), 2 and 3 function as “gatekeepers” of the MCU complex
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