Ablation of Impairs Metabolic Reprogramming and Proliferation of T Lymphocytes and Compromises Mouse Survival

Overview

Journal iScience

Publisher Cell Press

Date 2024 May 27

PMID 38799559

Authors

Ines Romero-Carraminana

Sonia Dominguez-Zorita

Pau B Esparza-Molto

Jose M Cuezva

Affiliations

Soon will be listed here.

Abstract

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 and 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.

References

Diebold L, Chandel N . Mitochondrial ROS regulation of proliferating cells. Free Radic Biol Med. 2016; 100:86-93. DOI: 10.1016/j.freeradbiomed.2016.04.198. View

Sena L, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman D . Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013; 38(2):225-36. PMC: 3582741. DOI: 10.1016/j.immuni.2012.10.020. View

Valdivieso Gonzalez D, Makowski M, Lillo M, Cao-Garcia F, Melo M, Almendro-Vedia V . Rotation of the c-Ring Promotes the Curvature Sorting of Monomeric ATP Synthases. Adv Sci (Weinh). 2023; 10(31):e2301606. PMC: 10625105. DOI: 10.1002/advs.202301606. View

Romero-Carraminana I, Esparza-Molto P, Dominguez-Zorita S, Nuevo-Tapioles C, Cuezva J . IF1 promotes oligomeric assemblies of sluggish ATP synthase and outlines the heterogeneity of the mitochondrial membrane potential. Commun Biol. 2023; 6(1):836. PMC: 10423274. DOI: 10.1038/s42003-023-05214-1. View

Santacatterina F, Sanchez-Cenizo L, Formentini L, Mobasher M, Casas E, Rueda C . Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state. Oncotarget. 2015; 7(1):490-508. PMC: 4808013. DOI: 10.18632/oncotarget.6357. View

Zhou B, Caudal A, Tang X, Chavez J, McMillen T, Keller A . Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts. J Clin Invest. 2022; 132(10). PMC: 9106352. DOI: 10.1172/JCI155333. View

Kuhlbrandt W . Structure and Mechanisms of F-Type ATP Synthases. Annu Rev Biochem. 2019; 88:515-549. DOI: 10.1146/annurev-biochem-013118-110903. View

Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko G, Rudka T . OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006; 126(1):177-89. DOI: 10.1016/j.cell.2006.06.025. View

Baixauli F, Acin-Perez R, Villarroya-Beltri C, Mazzeo C, Nunez-Andrade N, Gabande-Rodriguez E . Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses. Cell Metab. 2015; 22(3):485-98. PMC: 5026297. DOI: 10.1016/j.cmet.2015.07.020. View

10.

Chin R, Fu X, Pai M, Vergnes L, Hwang H, Deng G . The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014; 510(7505):397-401. PMC: 4263271. DOI: 10.1038/nature13264. View

11.

Cuezva J, Ortega A, Willers I, Sanchez-Cenizo L, Aldea M, Sanchez-Arago M . The tumor suppressor function of mitochondria: translation into the clinics. Biochim Biophys Acta. 2009; 1792(12):1145-58. DOI: 10.1016/j.bbadis.2009.01.006. View

12.

Garcia-Aguilar A, Martinez-Reyes I, Cuezva J . Changes in the Turnover of the Cellular Proteome during Metabolic Reprogramming: A Role for mtROS in Proteostasis. J Proteome Res. 2019; 18(8):3142-3155. DOI: 10.1021/acs.jproteome.9b00239. View

13.

Luis A, Izquierdo J, Ostronoff L, Salinas M, Santaren J, Cuezva J . Translational regulation of mitochondrial differentiation in neonatal rat liver. Specific increase in the translational efficiency of the nuclear-encoded mitochondrial beta-F1-ATPase mRNA. J Biol Chem. 1993; 268(3):1868-75. View

14.

Harms R, Morsey B, Boyer C, Fox H, Sarvetnick N . Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression. PLoS One. 2012; 7(12):e49897. PMC: 3515581. DOI: 10.1371/journal.pone.0049897. View

15.

Folmes C, Nelson T, Martinez-Fernandez A, Arrell D, Lindor J, Dzeja P . Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 2011; 14(2):264-71. PMC: 3156138. DOI: 10.1016/j.cmet.2011.06.011. View

16.

BOYER P . The ATP synthase--a splendid molecular machine. Annu Rev Biochem. 1997; 66:717-49. DOI: 10.1146/annurev.biochem.66.1.717. View

17.

Harner M, Korner C, Walther D, Mokranjac D, Kaesmacher J, Welsch U . The mitochondrial contact site complex, a determinant of mitochondrial architecture. EMBO J. 2011; 30(21):4356-70. PMC: 3230385. DOI: 10.1038/emboj.2011.379. View

18.

Torresano L, Santacatterina F, Dominguez-Zorita S, Nuevo-Tapioles C, Nunez-Salgado A, Esparza-Molto P . Analysis of the metabolic proteome of lung adenocarcinomas by reverse-phase protein arrays (RPPA) emphasizes mitochondria as targets for therapy. Oncogenesis. 2022; 11(1):24. PMC: 9085865. DOI: 10.1038/s41389-022-00400-y. View

19.

Bantug G, Galluzzi L, Kroemer G, Hess C . The spectrum of T cell metabolism in health and disease. Nat Rev Immunol. 2017; 18(1):19-34. DOI: 10.1038/nri.2017.99. View

20.

Walker J . The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans. 2013; 41(1):1-16. DOI: 10.1042/BST20110773. View