Seminar

Mitochondria-Lysosomal Crosstalk in the Immune System

Maria Mittelbrunn, PhD

For many years, mitochondria were viewed as semiautonomous organelles, required only for cellular energetics. This view has been displaced by the concept that mitochondria are fully integrated into the life of the cell and that mitochondrial function and stress response rapidly affect other organelles, and even other tissues.Lack of mitochondrial transcription factor A (Tfam) in T lymphocytes induces a severe decrease in mtDNA content, and a failure to express the key components of the electron transport chain, promoting severe OXPHOS dysfunction. Despite these mitochondrial abnormalities, Tfam-deficient T cells are viable, proliferate and rely on a metabolic program characterized by anaerobic glycolysis. By using this model, we have demonstrated a critical role for mitochondria in the regulation of lysosomal function (Baixauli et al Cell Metabolism 2015) . OXPHOS-deficient cells present abnormal lysosomal function, p62 and sphingomyelin accumulation, and disrupt endolysosomal trafficking pathways and autophagy, thus linking for the first time a primary mitochondrial dysfunction to lysosomal storage disorders (LSDs). Finally, we demonstrate that increasing NAD+ levels mitigate lysosome stress and reduce inflammatory responses in OXPHOS- deficient cells. Our results uncover a mechanism by which mitochondria regulate lysosome function and exacerbated inflammatory responses and identify new strategies to control undesired inflammatory responses. Reference: Baixauli et al. Cell Metab. 2015 Sep 1;22(3):485-98. “Mitochondrial Respiration Controls Lysosomal Function during Inflammatory T Cell Responses”. doi: 10.1016/j.cmet.2015.07.020