Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells
By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca<sup>2+</sup> homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca<sup>2+</sup> uniporter (MCU) is the pore-...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/9/7772 |
| Summary: | By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca<sup>2+</sup> homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca<sup>2+</sup> uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca<sup>2+</sup> uptake. Recently, MCU has been shown to modulate Ca<sup>2+</sup> signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of <i>Mcu</i> did not show impaired T cell responses in vitro or in vivo, indicating that ‘chronic’ loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of <i>Mcu</i> in murine Tregs results in a significant reduction both in mitochondrial Ca<sup>2+</sup> uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs. |
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| ISSN: | 1661-6596 1422-0067 |