Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses

Cell Metab. 2015 Sep 1;22(3):485-98. doi: 10.1016/j.cmet.2015.07.020. Epub 2015 Aug 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Respiration
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Gene Deletion
  • Immunity, Cellular
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / immunology*
  • Lysosomal Storage Diseases / pathology
  • Lysosomes / genetics
  • Lysosomes / immunology*
  • Lysosomes / pathology
  • Mice
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / immunology*
  • Sphingolipidoses / genetics
  • Sphingolipidoses / immunology*
  • Sphingolipidoses / pathology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Transcription Factors / genetics
  • Transcription Factors / immunology*

Substances

  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Transcription Factors
  • mitochondrial transcription factor A