Miro-1 Links Mitochondria and Microtubule Dynein Motors To Control Lymphocyte Migration and Polarity

ABSTRACT 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.

[1]  S. Bhatia,et al.  Mitochondrial localization and the persistent migration of epithelial cancer cells. , 2013, Biophysical journal.

[2]  F. Sánchez‐Madrid,et al.  End‐binding protein 1 controls signal propagation from the T cell receptor , 2012, The EMBO journal.

[3]  V. Robert,et al.  La signalisation calcique dans les lymphocytes T , 2012 .

[4]  H. Rieger,et al.  Calcium microdomains at the immunological synapse: how ORAI channels, mitochondria and calcium pumps generate local calcium signals for efficient T‐cell activation , 2011, The EMBO journal.

[5]  K. Min,et al.  Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons , 2011, Proceedings of the National Academy of Sciences.

[6]  G. Dubyak,et al.  Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle. , 2011, American journal of physiology. Heart and circulatory physiology.

[7]  Qian Cai,et al.  Regulation of axonal mitochondrial transport and its impact on synaptic transmission , 2011, Neuroscience Research.

[8]  F. Sánchez‐Madrid,et al.  The mitochondrial fission factor dynamin‐related protein 1 modulates T‐cell receptor signalling at the immune synapse , 2011, The EMBO journal.

[9]  M. Hoth,et al.  Immune synapses: mitochondrial morphology matters , 2011, The EMBO journal.

[10]  S. Campello,et al.  Adhesion shapes T cells for prompt and sustained T‐cell receptor signalling , 2010, The EMBO journal.

[11]  Beverly A. Teicher,et al.  CXCL12 (SDF-1)/CXCR4 Pathway in Cancer , 2010, Clinical Cancer Research.

[12]  K. Zinsmaier,et al.  Drosophila Miro Is Required for Both Anterograde and Retrograde Axonal Mitochondrial Transport , 2009, The Journal of Neuroscience.

[13]  Qian Cai,et al.  Moving or Stopping Mitochondria: Miro as a Traffic Cop by Sensing Calcium , 2009, Neuron.

[14]  D. Attwell,et al.  Miro1 Is a Calcium Sensor for Glutamate Receptor-Dependent Localization of Mitochondria at Synapses , 2009, Neuron.

[15]  R. Mondragón-Flores,et al.  Re-organization of mitochondria at the NK cell immune synapse. , 2009, Immunology letters.

[16]  Xinnan Wang,et al.  The Mechanism of Ca2+-Dependent Regulation of Kinesin-Mediated Mitochondrial Motility , 2009, Cell.

[17]  G. Hajnóczky,et al.  Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase , 2008, Proceedings of the National Academy of Sciences.

[18]  M. Mattson,et al.  Mitochondria in Neuroplasticity and Neurological Disorders , 2008, Neuron.

[19]  E. Gratton,et al.  Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms , 2008, The Journal of cell biology.

[20]  P. Bernardi,et al.  Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria , 2008, Proceedings of the National Academy of Sciences.

[21]  C. Sung,et al.  MTOC translocation modulates IS formation and controls sustained T cell signaling , 2008, The Journal of cell biology.

[22]  H. Petty,et al.  Observation of calcium microdomains at the uropod of living morphologically polarized human neutrophils using flash lamp‐based fluorescence microscopy , 2008, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[23]  M. Sixt,et al.  Rapid leukocyte migration by integrin-independent flowing and squeezing , 2008, Nature.

[24]  D. Chan,et al.  Functions and dysfunctions of mitochondrial dynamics , 2007, Nature Reviews Molecular Cell Biology.

[25]  I. Boldogh,et al.  Mitochondria on the move. , 2007, Trends in cell biology.

[26]  M. Hoth,et al.  T cell activation requires mitochondrial translocation to the immunological synapse , 2007, Proceedings of the National Academy of Sciences.

[27]  M. Cybulsky,et al.  Getting to the site of inflammation: the leukocyte adhesion cascade updated , 2007, Nature Reviews Immunology.

[28]  O. Barreiro,et al.  Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions , 2007, Immunological reviews.

[29]  S. Mañes,et al.  Establishment and Maintenance of Cell Polarity During Leukocyte Chemotaxis , 2007, Cell adhesion & migration.

[30]  S. Campello,et al.  Orchestration of lymphocyte chemotaxis by mitochondrial dynamics , 2006, The Journal of experimental medicine.

[31]  A. Ruusala,et al.  The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. , 2006, Biochemical and biophysical research communications.

[32]  T. Schwarz,et al.  Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent , 2006, The Journal of cell biology.

[33]  C. Cabañas,et al.  Synaptic clusters of MHC class II molecules induced on DCs by adhesion molecule-mediated initial T-cell scanning. , 2005, Molecular biology of the cell.

[34]  T. Kinashi,et al.  Intracellular signalling controlling integrin activation in lymphocytes , 2005, Nature Reviews Immunology.

[35]  Yasunori Hayashi,et al.  The Importance of Dendritic Mitochondria in the Morphogenesis and Plasticity of Spines and Synapses , 2004, Cell.

[36]  Michael P. Sheetz,et al.  Axonal mitochondrial transport and potential are correlated , 2004, Journal of Cell Science.

[37]  E. Holzbaur,et al.  A Direct Interaction between Cytoplasmic Dynein and Kinesin I May Coordinate Motor Activity* , 2004, Journal of Biological Chemistry.

[38]  Miguel Vicente-Manzanares,et al.  Role of the cytoskeleton during leukocyte responses , 2004, Nature Reviews Immunology.

[39]  A. Ruusala,et al.  Atypical Rho GTPases Have Roles in Mitochondrial Homeostasis and Apoptosis* , 2003, The Journal of Biological Chemistry.

[40]  I. Vernos,et al.  Dynactin is required for bidirectional organelle transport , 2003, The Journal of cell biology.

[41]  María Yáñez-Mó,et al.  Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes , 2002, The Journal of cell biology.

[42]  A. Khodjakov,et al.  Centrosome reorientation in wound-edge cells is cell type specific. , 2002, Molecular biology of the cell.

[43]  C. Cabañas,et al.  LFA‐1 integrin and the microtubular cytoskeleton are involved in the Ca2+‐mediated regulation of the activity of the tyrosine kinase PYK2 in T cells , 2002, Journal of leukocyte biology.

[44]  F. Sánchez‐Madrid,et al.  A Role for the Rho-p160 Rho Coiled-Coil Kinase Axis in the Chemokine Stromal Cell-Derived Factor-1α-Induced Lymphocyte Actomyosin and Microtubular Organization and Chemotaxis1 , 2002, The Journal of Immunology.

[45]  Michael D Schaller,et al.  Paxillin: a focal adhesion-associated adaptor protein , 2001, Oncogene.

[46]  Hiroaki Mitsuya,et al.  Diverse Transcriptional Response of CD4+ T Cells to Stromal Cell-Derived Factor (SDF)-1: Cell Survival Promotion and Priming Effects of SDF-1 on CD4+ T Cells1 , 2001, The Journal of Immunology.

[47]  C. Cabañas,et al.  Paxillin Localizes to the Lymphocyte Microtubule Organizing Center and Associates with the Microtubule Cytoskeleton* , 2000, The Journal of Biological Chemistry.

[48]  F. Maxfield,et al.  Ca2+-dependent myosin II activation is required for uropod retraction during neutrophil migration. , 2000, Journal of cell science.

[49]  Sheila M. Thomas,et al.  Binding of paxillin to α4 integrins modifies integrin-dependent biological responses , 1999, Nature.

[50]  G. Rutter,et al.  Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[51]  W. Saxton,et al.  Cytoplasmic dynein, the dynactin complex, and kinesin are interdependent and essential for fast axonal transport. , 1999, Molecular biology of the cell.

[52]  S. Karki,et al.  Cytoplasmic dynein and dynactin in cell division and intracellular transport. , 1999, Current opinion in cell biology.

[53]  F. Sánchez‐Madrid,et al.  Leukocyte polarization in cell migration and immune interactions , 1999, The EMBO journal.

[54]  L. Ashman,et al.  Regulation of Endothelial Cell Motility by Complexes of Tetraspan Molecules CD81/TAPA-1 and CD151/PETA-3 with α3β1 Integrin Localized at Endothelial Lateral Junctions , 1998, The Journal of cell biology.

[55]  N. Hirokawa,et al.  Golgi Vesiculation and Lysosome Dispersion in Cells Lacking Cytoplasmic Dynein , 1998, The Journal of cell biology.

[56]  F. Sánchez‐Madrid,et al.  Moesin Interacts with the Cytoplasmic Region of Intercellular Adhesion Molecule-3 and Is Redistributed to the Uropod of T Lymphocytes during Cell Polarization , 1997, The Journal of cell biology.

[57]  M. Hoth,et al.  Mitochondrial Regulation of Store-operated Calcium Signaling in T Lymphocytes , 1997, The Journal of cell biology.

[58]  T. Springer,et al.  A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1) , 1996, The Journal of experimental medicine.

[59]  M. Nieto,et al.  Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway , 1995, The Journal of cell biology.

[60]  K. Fogarty,et al.  Chemotaxis of newt eosinophils: calcium regulation of chemotactic response. , 1993, The American journal of physiology.

[61]  A. Craig,et al.  ICAM-3 interacts with LFA-1 and regulates the LFA-1/ICAM-1 cell adhesion pathway , 1993, The Journal of cell biology.

[62]  H. Peng,et al.  The function of mitochondria in presynaptic development at the neuromuscular junction. , 2008, Molecular biology of the cell.

[63]  A. Engel.  The neuromuscular junction. , 2008, Handbook of clinical neurology.

[64]  Sakae Tanaka,et al.  Integrin alpha4beta1 promotes focal adhesion kinase-independent cell motility via alpha4 cytoplasmic domain-specific activation of c-Src. , 2005, Molecular and cellular biology.

[65]  F. Sánchez‐Madrid,et al.  Measurement of the levels of polymerized actin (F-actin) in chemokine-stimulated lymphocytes and GFP-coupled cDNA transfected lymphoid cells by flow cytometry. , 2004, Methods in molecular biology.

[66]  F. Sánchez‐Madrid,et al.  The two poles of the lymphocyte: specialized cell compartments for migration and recruitment. , 1998, Cell adhesion and communication.

[67]  Sakae Tanaka,et al.  Integrin (cid:2) 4 (cid:3) 1 Promotes Focal Adhesion Kinase-Independent Cell Motility via (cid:2) 4 Cytoplasmic Domain-Specific Activation of c-Src‡ , 2022 .