Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells

Abstract

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca2+ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca2+ uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca2+ uptake. Recently, MCU has been shown to modulate Ca2+ 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 Mcu 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 Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca2+ 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.

Spatial and single-cell explorations uncover prognostic significance and immunological functions of mitochondrial calcium uniporter in breast cancer

“…Serving as a pivotal organelle within cells, mitochondria possess an intricate mechanism to maintain Ca 2+ homeostasis. Besides the voltage-dependent Ca 2+ channels present in the outer mitochondrial membrane, the MCU stands out as the principal pathway responsible for the uptake of Ca 2+ into mitochondria [ 9 ]. The MCU not only governs mitochondrial Ca 2+ levels but also exerts regulatory control over intracellular signaling cascades, which converge at this organelle, ultimately influencing cellular processes such as proliferation, differentiation, and apoptosis.…”