Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Supervisors info:
Παναγιώτης Βεργίνης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης, Επιβλέπων
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αριστείδης Ηλιόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Dissecting regulatory T cell mitochondrial malfunction in autoimmunity
Translated title:
Dissecting regulatory T cell mitochondrial malfunction in autoimmunity
Summary:
Autoimmune diseases (ADs) are a heterogeneous group of multifactorial, potentially life-threatening clinical syndromes that emerge from the breakdown of self-tolerance mechanisms. Among the various mechanisms implicated in autoimmunity, regulatory T cells (Treg) are a specific cellular subset with protective role, whose reduced number and/or aberrant behavior are hallmarks of this condition. Recently, the unique metabolic profile of Tregs has gained much attention, since these cells depend on certain metabolic traits for their fitness, with mitochondrial metabolism being vital for their T cell suppression capacity, stability, and survival. Previous studies by our research group have uncovered the existence of a Treg cell metabolic reprogramming in autoimmunity, characterized by compromised mitochondrial function and an ensuing increase in mitochondrial oxidative stress, resulting in impaired lysosomal function, DNA damage response and cell death. However, the specific upstream mechanisms triggering Treg mitochondrial dysfunction in ADs remain elusive. To answer this question in this study we provide a detailed molecular characterization and metabolic phenotyping of Tregs isolated from mice with experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. Our findings demonstrate the existence of specific defects in electron transport chain (ETC) complexes I, II, and IV, as indicated by the markedly decreased expression of several complexes’ components. Furthermore, we reveal dysregulated expression of important Ca2+ transfer mediators from the ER to the cytosol and the mitochondria and critically decreased expression of the major mitochondrial calcium uniporter (MCU). These results suggest low mitochondrial Ca2+ accumulation, which may contribute to the observed ETC deficiency. Our multi-omics analyses, combined with flow cytometry-based assays also indicate a wide-scale metabolic changes characterized by a possible upregulation of anaerobic glycolysis and fatty acid metabolism in Tregs from diseased mice. Collectively, our data bring into focus impairment in respiratory chain complexes as an important feature of autoimmune Tregs leading to mitochondrial collapse, and highlight disturbed mitochondrial Ca2+ as its potential coordinator. Further investigation of these mechanisms may lead to the development of novel therapies for ADs selectively modulating Tregs.
Main subject category:
Health Sciences
Keywords:
Immune regulation, Autoimmunity, Immunometabolism, Regulatory T cells, Mitochondria
Number of references:
154
File:
File access is restricted until 2025-09-26.
Nakou_Evangelia_MSc.pdf
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File access is restricted until 2025-09-26.
