Differentiation-Induced Rearrangement of the Mitochondrial Calcium Uniporter Complex Regulates T-Cell-Mediated Immunity

von Magdalena Shumanska
Dissertation
Datum der mündl. Prüfung:2022-12-16
Erschienen:2023-01-20
Betreuer:Dr. Ivan Prof Bogeski
Gutachter:Dr. Ivan Prof Bogeski
Gutachter:Prof. Dr. Thomas Meyer
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-9677

 

 

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Description:Main doctoral thesis

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Zusammenfassung

Englisch

CD4+ T-cells are an important cell type involved in proper mediation of the human adaptive immune system. Activation of CD4+ T-cells is a regulated process which includes a tightly controlled cytosolic calcium (Ca2+) increase. Multiple fundamental T-cell processes are governed by Ca2+ ions, including cell subtype differentiation, energy production, proliferation, migration, and effector molecule secretion. Mitochondria are the main Ca2+ buffering system in T-cells, allowing proper regulation and support of cellular metabolic demands. The mitochondrial calcium uniporter (MCU) complex is the main regulator of mitochondrial Ca2+ influx in the inner mitochondrial membrane of T-cells; thus, MCU alterations could be associated with mediation of T-cell immune responses. However, the exact role of MCU in Tcells is poorly understood. This Doctoral Thesis aimed to explore the role of MCU in isolated primary human CD4+ T-cells by generating a model of transient MCUa downregulation and investigating its effect on CD4+ T-cell mitochondrial metabolism and function. We show that activation of T-cells causes a rearrangement of the MCU complex, leading to elevated mitochondrial Ca2+ uptake and increased mitochondrial bioenergetics. Downregulation of MCU diminishes this effect and suppresses mitochondrial respiration, ATP generation and proinflammatory T-cell function. Additionally, our results show that an elevation of the mitochondrial-AAA protease AFG3L2 acts as a compensatory mechanism upon MCUa downregulation, controlling MCU complex stability via EMRE proteolysis. Finally, downregulation of MCUa in primary rat effector T-cells not only validated the results obtained in human T-cells but also caused a delay in disease onset in an experimental model of multiple sclerosis in vivo. In conclusion, mitochondrial Ca2+ influx through the MCU complex is essential for proper T-cell function and metabolism, and is involved in mediating autoimmunity. Targeting MCU in T-cells could prove beneficial for suppression of progressive autoimmune disease.
Keywords: mitochondria; calcium; autoimmunity; T-cells; metabolism