ArticleFrontiers in immunology2022
Notch1 Modulation of Cellular Calcium Regulates Mitochondrial Metabolism and Anti-Apoptotic Activity in T-Regulatory Cells.
Article in Frontiers in immunology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 21 citations in OpenAlex.
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- Effect of micronutrients on the risk of Graves' disease: a Mendelian randomization study.Frontiers in nutrition · 2024Article
- Leptin, Adiponectin, and Melatonin Modulate Colostrum Lymphocytes in Mothers with Obesity.International journal of molecular sciences · 2023Article
- Identification and Validation of a Mitochondria Calcium Uptake-Related Gene Signature for Predicting Prognosis in COAD.Journal of Cancer · 2023Article
- Thyroid hormones and minerals in immunocorrection of disorders in autoimmune thyroid diseases.Frontiers in endocrinology · 2023Review
- Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival.Life science alliance · 2022Article
- Sirtuin1 meditated modification of Notch1 intracellular domain regulates nucleolar localization and activation of distinct signaling cascades.Frontiers in cell and developmental biology · 2022Article
- Endoplasmic reticulum stress related IncRNA signature predicts the prognosis and immune response evaluation of uterine corpus endometrial carcinoma.Frontiers in oncology · 2022Article
- The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity.Frontiers in immunology · 2022Review
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As the major hub of metabolic activity and an organelle sequestering pro-apoptogenic intermediates, mitochondria lie at the crossroads of cellular decisions of death and survival. Intracellular calcium is a key regulator of these outcomes with rapid, uncontrolled uptake into mitochondria, activating pro-apoptotic cascades that trigger cell death. Here, we show that calcium uptake and mitochondrial metabolism in murine T-regulatory cells (Tregs) is tuned by Notch1 activity. Based on analysis of Tregs and the HEK cell line, we present evidence that modulation of cellular calcium dynamics underpins Notch1 regulation of mitochondrial homeostasis and consequently anti-apoptotic activity. Targeted siRNA-mediated ablations reveal dependency on molecules controlling calcium release from the endoplasmic reticulum (ER) and the chaperone, glucose-regulated protein 75 (Grp75), the associated protein Voltage Dependent Anion Channel (VDAC)1 and the Mitochondrial Calcium Uniporter (MCU), which together facilitate ER calcium transfer and uptake into the mitochondria. Endogenous Notch1 is detected in immune-complexes with Grp75 and VDAC1. Deficits in mitochondrial oxidative and survival in Notch1 deficient Tregs, were corrected by the expression of recombinant Notch1 intracellular domain, and in part by recombinant Grp75. Thus, the modulation of calcium dynamics and consequently mitochondrial metabolism underlies Treg survival in conditions of nutrient stress. This work positions a key role for Notch1 activity in these outcomes.
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