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Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses

Published on Sep 1, 2015in Cell Metabolism22.415
· DOI :10.1016/j.cmet.2015.07.020
Francesc Baixauli10
Estimated H-index: 10
(ISCIII: Carlos III Health Institute),
Rebeca Acín-Pérez30
Estimated H-index: 30
(ISCIII: Carlos III Health Institute)
+ 10 AuthorsMaría Mittelbrunn32
Estimated H-index: 32
(ISCIII: Carlos III Health Institute)
Abstract
Summary 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.
  • References (42)
  • Citations (71)
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