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 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

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 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

The Twannberg iron meteorite strewn field in the Swiss Jura mountains: insights for Quaternary environmental conditions

The ~ 10 km 2 strewn field of the Twannberg type IIG iron meteorite is located in the Swiss Jura Mountains, 30 km northwest of Bern. The strewn field has been mapped by a group of citizen scientists since 2006, yielding more than 2000 meteorite fragments with a total mass of 152.7 kg until the end of 2022. With a terrestrial age of 176 ± 19 ka and a minimum pre-atmospheric mass of ~ 250 t, the Twannberg meteorite is a local time marker in an area with a poorly-known paleoenvironmental history. The Twannberg strewn field is located just outside of the maximum extent of ice during the Last Glacial Maximum (LGM). On the Mont Sujet, meteorites are size-sorted in a 6-km long section of the primary strewn field (altitude 945-1370 m a.s.l.), indicating a fall direction from east-northeast to west-southwest (azimuth approximately 250°). On the Twannberg plateau and in the Twannbach gorge, meteorites are not size-sorted and occur in a ~ 5.7-km long area associated with till and recent stream sediments (altitude 430-1075 m a.s.l.). The mass distribution of meteorites on the Twannberg plateau demonstrate that these meteorites were not found where they fell but that they must have been transported up to several km by glacier ice flow after the fall. The distribution of meteorites and of glacially transported Alpine clasts on the Mont Sujet and on the Chasseral chain indicates the presence of local ice caps and of an approximately 200-m higher Alpine ice surface with respect to the LGM at the time of fall. This high ice level during MIS 6 (Marine Isotopic Stage 6, 191-130 ka) indicated by the meteorite distribution is consistent with surface exposure ages of 50-144 ka from nearby resting erratic boulders at altitudes of up to 1290 m a.s.l., including the newly dated Jobert boulder (63 ka). These boulders indicate an ice level ~ 400 m higher than during LGM at a time not later than MIS 6. Post-LGM luminescence ages of loesscontaining meteorites on the Mont Sujet and 14 C ages of materials associated with meteorite finds indicate relatively young pedoturbation and increased oxidation of meteorites since ~ 7300 cal BP, possibly correlated with deforestation and enhanced erosion resulting from increased human activities since the Neolithic. This study shows that Twannberg meteorites in their palaeoenvironmental context provide valuable information about ice levels and transport directions during MIS 6 and about their interaction with the post-LGM environmental conditions. The unique Twannberg strewn field has the potential to reveal more valuable information