Editors' ChoiceCell Biology

Inflammatory Mitochondria

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Sci. Signal.  18 Jan 2011:
Vol. 4, Issue 156, pp. ec15
DOI: 10.1126/scisignal.4156ec15

Detection of pathogen- and danger-associated molecular patterns by the NLRP3 inflammasome leads to the activation of the protease caspase-1, which subsequently processes the cytokine interleukin-1β (IL-1β) into its active form. The NLRP3 inflammasome has been proposed to be activated by reactive oxygen species (ROS), although the source of ROS had not been identified. Blocking respiratory enzymes in mitochondria can lead to the production of ROS, and Zhou et al. found that the secretion of IL-1β by human THP1 macrophage cells increased after treatment with an inhibitor against complex I or III but not one against complex II. This effect was absent in THP1 cells transfected with short hairpin RNA (shRNA) directed against NLRP3 or caspase-1 or bone marrow–derived macrophages from Nlrp3–/– mice. Damaged mitochondria, such as those generating ROS, are removed by mitophagy (a form of autophagy specifically pertaining to mitochondria). Inhibition of mitophagy in THP1 cells, whether by treatment with 3-methyladenine or shRNA-mediated knockdown of the autophagy components beclin 1 and ATG5, elicited the accumulation of damaged mitochondria and increased secretion of IL-1β. Activation of the inflammasome by various stimuli induced the relocation of NLRP3 from the cytosol to the perinuclear space and its colocalization and cofractionation with markers for the endoplasmic reticulum and mitochondria. Voltage-dependent anion channels (VDACs) are required for the release of mitochondrially generated ROS into the cytosol, and THP-1 cells deficient in VDAC1 showed decreased caspase-1 activation and IL-1β secretion. Because VDACs have a previously established role in the Bax-mediated induction of apoptosis, the authors note that it will be important to elucidate the mechanisms that determine whether activation of VDACs initiates inflammatory or apoptotic events.

R. Zhou, A. S. Yazdi, P. Menu, J. Tschopp, A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011). [PubMed]