期刊
FRONTIERS IN PHARMACOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.734078
关键词
mitochondrial calcium uniporter (MCU); store-operated Ca2+ entry; mitochondria; oxidative phosphorylation; calcium (Ca2+); immunometabolism; mitochondrial Ca2+ handling
资金
- Deutsche Forschungsgemeinschaft (German Research Foundation) [SFB-TRR 124/3 2021 210879364, SFB-TRR 338/1 2021 452881907, VA882/2-1, SFB 1027, SFB 1190, IRTG1816, DU1839/2-1, SFB 894, SFB-TRR 219, Ma 2528/7-1]
- Federal Ministry of Education and Research (BMBF) [01EO1504]
The study demonstrates that mitochondrial Ca2+ uptake is largely dispensable for murine T cell function, despite an increase in cytosolic Ca2+ levels with genetic inactivation of MCU. The discrepancy between this study and previous reports suggests compensatory mechanisms in MCU-deficient mice and/or off-target effects of current MCU inhibitors.
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.
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