Morlino G.,CSIC - National Center for Metallurgical Research |
Morlino G.,Instituto Investigacion Sanitaria Princesa |
Barreiro O.,CSIC - National Center for Metallurgical Research |
Barreiro O.,Instituto Investigacion Sanitaria Princesa |
And 12 more authors.
Molecular and Cellular Biology | Year: 2014
The recruitment of leukocytes to sites of inflammation is crucial for a functional immune response. In the present work, we explored the role of mitochondria in lymphocyte adhesion, polarity, and migration. We show that during adhesion to the activated endothelium under physiological flow conditions, lymphocyte mitochondria redistribute to the adhesion zone together with the microtubule-organizing center (MTOC) in an integrin-dependent manner. Mitochondrial redistribution and efficient lymphocyte adhesion to the endothelium require the function of Miro-1, an adaptor molecule that couples mitochondria to microtubules. Our data demonstrate that Miro-1 associates with the dynein complex. Moreover, mitochondria accumulate around the MTOC in response to the chemokine CXCL12/SDF-1α this redistribution is regulated by Miro-1. CXCL12-dependent cell polarization and migration are reduced in Miro-1-silenced cells, due to impaired myosin II activation at the cell uropod and diminished actin polymerization. These data point to a key role of Miro-1 in the control of lymphocyte adhesion and migration through the regulation of mitochondrial redistribution. © 2014, American Society for Microbiology.
Baixauli F.,Centro Nacional Investigaciones Cardiovasculares Carlos III CNIC |
Baixauli F.,Instituto Investigacion Sanitaria Princesa |
Acin-Perez R.,Centro Nacional Investigaciones Cardiovasculares Carlos III CNIC |
Villarroya-Beltri C.,Centro Nacional Investigaciones Cardiovasculares Carlos III CNIC |
And 13 more authors.
Cell Metabolism | Year: 2015
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. © 2015 Elsevier Inc.