Ablation of Atp5if1 impairs metabolic reprogramming and proliferation of T lymphocytes and compromises mouse survival

• Published in: iScience Vol. 27; no. 6; p. 109863
• Main Authors: Romero-Carramiñana, Inés, Dominguez-Zorita, Sonia, Esparza-Moltó, Pau B., Cuezva, José M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-06-2024; Elsevier
• Subjects: Biological sciences; Immunology; Molecular biology; Physiology; Biological sciences; Physiology; Immunology; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.109863

T cells experience metabolic reprogramming to an enhanced glycolysis upon activation. Herein, we have investigated whether ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of mitochondrial ATP synthase, participates in rewiring T cells to a particular metabolic phenotype. We show that the activation of naive CD4+ T lymphocytes both in vitro and in vivo is accompanied by a sharp upregulation of IF1, which is expressed only in Th1 effector cells. T lymphocytes of conditional CD4+-IF1-knockout mice display impaired glucose uptake and flux through glycolysis, reducing the biogenesis of mitochondria and cellular proliferation after activation. Consequently, mice devoid of IF1 in T lymphocytes cannot mount an effective Th1 response against bacterial infection compromising their survival. Overall, we show that the inhibition of a fraction of ATP synthase by IF1 regulates metabolic reprogramming and functionality of T cells, highlighting the essential role of IF1 in adaptive immune responses.
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•Activated CD4+ IF1-KO cells prevent ATP synthase inhibition impairing glucose uptake•Activated CD4+ IF1-KO cells limit aerobic glycolysis and mitochondrial biogenesis•The proliferation of activated CD4+ IF1-KO cells is impaired in vitro and in vivo•CD4+ IF1-KO mice have an arrested Th1 immune response against bacterial infection
Biological sciences; Physiology; Molecular biology; Immunology