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 subpopulationspecific 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