title: Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses.
abstract: The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4(+) T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation, and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward proinflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD(+) levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify strategies for intervention in mitochondrial-related diseases.
authors: Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain; Servicio de Inmunología, Instituto Investigación Sanitaria Princesa, Madrid 28006, Spain.
authors: Francesc
authors: F
authors: Baixauli
authors: Cardiovascular Metabolism Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors: Rebeca
authors: R
authors: Acín-Pérez
authors: Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain; Servicio de Inmunología, Instituto Investigación Sanitaria Princesa, Madrid 28006, Spain.
authors: Carolina
authors: C
authors: Villarroya-Beltrí
authors: Department of Immunology, IIS-Fundación Jiménez Díaz, Madrid 28040, Spain.
authors: Carla
authors: C
authors: Mazzeo
authors: Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain; Servicio de Inmunología, Instituto Investigación Sanitaria Princesa, Madrid 28006, Spain.
authors: Norman
authors: N
authors: Nuñez-Andrade
authors: Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
authors: Enrique
authors: E
authors: Gabandé-Rodriguez
authors: Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain.
authors: Maria Dolores
authors: MD
authors: Ledesma
authors: Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid 28041, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
authors: Alberto
authors: A
authors: Blázquez
authors: Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid 28041, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid 28029, Spain.
authors: Miguel Angel
authors: MA
authors: Martin
authors: CIC bioGUNE, CIBERehd, Derio 48160, Spain; IKERBASQUE Research Foundation, Bilbao 48011, Spain.
authors: Juan Manuel
authors: JM
authors: Falcón-Pérez
authors: Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors: Juan Miguel
authors: JM
authors: Redondo
authors: Cardiovascular Metabolism Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors: Jose Antonio
authors: JA
authors: Enríquez
authors: Signaling and Inflammation Program, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain. Electronic address: mmittelbrunn@externo.cnic.es.
authors: Maria
authors: M
authors: Mittelbrunn
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D007111:Immunity, Cellular; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008247:Lysosomes / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology*; D013106:Sphingolipidoses / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A