title: Stomatin-like protein 2 deficiency in T cells is associated with altered mitochondrial respiration and defective CD4+ T cell responses.
abstract: Stomatin-like protein 2 (SLP-2) is a mostly mitochondrial protein that regulates mitochondrial biogenesis and function and modulates T cell activation. To determine the mechanism of action of SLP-2, we generated T cell-specific SLP-2-deficient mice. These mice had normal numbers of thymocytes and T cells in the periphery. However, conventional SLP-2-deficient T cells had a posttranscriptional defect in IL-2 production in response to TCR ligation, and this translated into reduced CD4(+) T cell responses. SLP-2 deficiency was associated with impaired cardiolipin compartmentalization in mitochondrial membranes, decreased levels of the NADH dehydrogenase (ubiquinone) iron-sulfur protein 3, NADH dehydrogenase (ubiquinone) 1β subcomplex subunit 8, and NADH dehydrogenase (ubiquinone) 1α subcomplex subunit 9 of respiratory complex I, and decreased activity of this complex as well as of complex II plus III of the respiratory chain. In addition, SLP-2-deficient T cells showed a significant increase in uncoupled mitochondrial respiration and a greater reliance on glycolysis. Based on these results, we propose that SLP-2 organizes the mitochondrial membrane compartmentalization of cardiolipin, which is required for optimal assembly and function of respiratory chain complexes. This function, in T cells, helps to ensure proper metabolic response during activation.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Darah A
authors.initials: DA
authors.lastname: Christie
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mitsopoulos
authors.forename: Julianna
authors.initials: J
authors.lastname: Blagih
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Dunn
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.forename: Grant M
authors.initials: GM
authors.lastname: Hatch
authors.forename: Joaquín
authors.initials: J
authors.lastname: Madrenas
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002308:Cardiolipins / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D001798:Blood Proteins; D002308:Cardiolipins; D008565:Membrane Proteins; C406287:STOML2 protein, human