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Cuezva Marcos, Jose ManuelSupervisor

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IF1 como regulador de la función bioenergética mitocondrial y su implicación en el sistema inmune

Date read: 2023-10-27 {_iPublic_txt_centro_}: | ID: 10486/712831

Author: Romero CarramiÑana, Ines

Director: Cuezva Marcos, Jose Manuel

Abstract

Esta tesis tiene embargado el acceso al texto completo hasta el 27-04-2025 (General); Mitochondria play a central role in cellular physiology, acting as metabolic and signaling hubs. Mitochondrial ATP synthase integrates many of these functions, including ATP synthesis by oxidative phosphorylation, the execution of cell death and the production of signaling molecules. The ATPase inhibitory factor 1 (IF1) is the main physiological inhibitor of ATP synthase. One goal of this study has been to elucidate the function of IF1 in the regulation of ATP synthase and its implications on mitochondrial bioenergetics and structure. To this aim, we have generated two knockout human cell lines for IF1 and a global IF1-knockout mouse model. We demonstrate that in cells and tissues where IF1 is expressed, active and inactive fractions of IF1- bound ATP synthase coexist in the same mitochondria. The interaction of IF1 with ATP synthase regulates the activity of the enzyme, the rate of mitochondrial respiration, mitochondrial membrane potential (ΔΨm), and the production of reactive oxygen species. Furthermore, IF1 controls the oligomerization of ATP synthase in IF1-expressing cells and influences the structure of mitochondrial cristae. Lastly, we demonstrate that the intramitochondrial distribution of IF1 correlates with cristae microdomains of high ΔΨm, partially explaining the heterogeneous distribution of ΔΨm in mitochondria. IF1 exhibits a tissue- and species-specific expression pattern. Moreover, it is overexpressed in cell types that acquire a proliferative phenotype and undergo metabolic reprogramming towards an increased glycolysis, such as cancer cells or reprogrammed stem cells. Immune cells adopt a similar phenotype upon activation. Therefore, another objective of this study has been to characterize the expression and function of IF1 in the innate and adaptive immune systems, specifically in murine bone marrow-derived macrophages (BMDM) and CD4+ T lymphocytes. Quiescent CD4+ lymphocytes do not express IF1, but its expression is induced upon activation and differentiation into the effector Th1 subtype. To study the implications of IF1 in the activation of T lymphocytes, we have generated the first specific knockout mouse model of IF1 in T lymphocytes (CD4-IF1-KO). Murine IF1-deficient CD4+ lymphocytes cannot activate and proliferate properly, both in vitro and in vivo, due to the dysregulation of the ATP synthase activity. As a result, CD4-IF1-KO mice have a compromised survival against infections. On the contrary, quiescent, inflammatory and anti-inflammatory BMDM, despite presenting large differences in metabolic activity, show no differences in the high expression levels of IF1. However, genetic ablation of IF1 in BMDM alters their mitochondrial structure and bioenergetics, predisposing them towards a more inflammatory phenotype. Overall, these results position IF1- mediated regulation of ATP synthase activity as a key mechanism to understand the metabolic and functional versatility of immune cells (Summary)

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