Editors' ChoiceImmunology

More roles for mitochondria in the immune response

Sci. Signal.  13 Sep 2016:
Vol. 9, Issue 445, pp. ec208
DOI: 10.1126/scisignal.aai9319

In addition to being the energy-producing organelles of cells, mitochondria are involved in cell death and reactive oxygen species (ROS) production, and they act as platforms for innate immune responses. Electron flow through the electron transport chain (ETC), a series of multiprotein complexes (I through V) in the inner mitochondrial membrane, is required for efficient ATP production. Macrophages are among the first responding cells of the immune system (see Holmbeck and Shadel). Through an array of pattern recognition receptors, including the Toll-like receptors (TLRs) and multiprotein complexes known as inflammasomes, these cells detect pathogen-derived molecules and produce inflammatory cytokines. They also engulf and kill bacteria. Garaude et al. found that the phagocytosis of live bacteria by macrophages destabilized the assembly of complex I in the ETC, reducing its activity, but increased the activity of complex II. These changes depended on phagosomal NADPH oxidase (NOX)–mediated ROS production and the tyrosine kinase Fgr. Phagocytosis of dead bacteria did not enhance complex II activity, but exposing macrophages to bacterial RNA stimulated complex II activity through a process that required TLR and inflammasome signaling. Succinate dehydrogenase (SDH), which catalyzes the conversion of the metabolite succinate to fumarate, is one of the subunits of complex II. Inhibition of SDH in macrophages with the inhibitor NPA resulted in decreased complex II activity in response to cell infection with Escherichia coli. Mice treated with NPA and then infected with Salmonella enterica Typhymurium died in greater numbers than did their vehicle-treated counterparts and had decreased amounts of inflammatory cytokines in their serum. Similar defects in inflammatory cytokine production were observed in NPA-treated mice infected with E. coli. Together, these data suggest that the detection of live bacteria by macrophages remodels and alters the activity of complexes in the ETC, which is required for an optimal inflammatory response.

J. Garaude, R. Acín-Pérez, S. Martínez-Cano, M. Enamorado, M. Ugolini, E. Nistal-Villán, S. Hervás-Stubbs, P. Pelegrín, L. E. Sander, J. A. Enríquez, D. Sancho, Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense. Nat. Immunol. 17, 1037–1045 (2016). [PubMed]

M. A. Holmbeck, G. S. Shadel, Mitochondria provide a ‘complex’ solution to a bacterial problem. Nat. Immunol. 17, 1009–1010 (2016). [PubMed]