Orchestration of lymphocyte chemotaxis by mitochondrial dynamics

Abstract

Lymphocyte traffic is required to maintain homeostasis and perform appropriate immunological reactions. To migrate into inflamed tissues, lymphocytes must acquire spatial and functional asymmetries. Mitochondria are highly dynamic organelles that distribute in the cytoplasm to meet specific cellular needs, but whether this is essential to lymphocyte functions is unknown. We show that mitochondria specifically concentrate at the uropod during lymphocyte migration by a process involving rearrangements of their shape. Mitochondrial fission facilitates relocation of the organelles and promotes lymphocyte chemotaxis, whereas mitochondrial fusion inhibits both processes. Our data substantiate a new role for mitochondrial dynamics and suggest that mitochondria redistribution is required to regulate the motor of migrating cells.

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

“…6E). Maintenance of DCm not only prevents cell-intrinsic apoptosis pathways (8,9), but it also is critical for the generation of mROS (9)(10)(11). Because sodium pyruvate has intrinsic antioxidant capacity (24), it was not possible to reliably assess its effect on cellular or mROS levels.…”

“…Next we tested how metabolic profiles of CD4 + T cells related to their migration, which is highly ATP-dependent and fundamental to immune surveillance of peripheral tissues (10,11). At bulk and single-cell levels (using a Transwell assay and microfluidic system, respectively), we first defined spontaneous and chemokine (CXCL12)-directed migratory properties of CD4 + T cell populations.…”

“…Shuttling between normoxia and hypoxia, mitochondria of EM CD4 + T cells have to maintain ATP fueling of bioenergetically demanding processes, such as migration (10,11). At the same time, maintaining DCm and tonic mROS production throughout substantial cyclic changes in oxygen availability poses a unique, nonbioenergetic metabolic challenge to EM CD4 + T cells.…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…36,37 This would suggest that mitochondrial fusion-fission plays a specific role in morphogenesis, additional to its influence on movement of the organelle. Similarly, Campello et al 38 recently demonstrated that the shape of the mitochondrial reticulum regulates the ability of lymphocytes to migrate. Following chemotactic stimulation, mitochondria accumulate at the uropod of polarized lymphocytes.…”

“…Moreover, induction of mitochondrial fission is per se able to induce a polarized appearance of these lymphocytes, further strengthening the role of mitochondrial fusion-fission in cellular morphogenesis and ultimately function. 38 Production of ROS and lifespan. Mitochondria, together with peroxisomes, are the major source of ROS.…”