Fig. 1: NF-κB signaling and the mitochondrial checkpoint.

In caspase-incompetent scenarios, the loss of mitochondrial integrity can elicit various inflammatory effects including (but not limited to) NF-κB activation. Such a process does not rely on alterations of mitochondrial bioenergetics or calcium buffering, but rather involves the K63-linked ubiquitination (K63-Ub) of various outer mitochondrial membrane (OMM) proteins and the consequent recruitment of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG, best known as NEMO). At least in some cells, this results in the activation of a negative feedback loop promoting the mitophagic disposal of permeabilized mitochondria via NF-κB-dependent sequestosome 1 (SQSTM1, best known as p62) expression. Thus, mitochondrial integrity stands at a central position in the preservation of inflammatory homeostasis. BAK1, BCL2 antagonist/killer 1 (BAK1); BAX, BCL2 associated X, apoptosis regulator; CXCL1, C-X-C motif chemokine ligand 1; IKBα (official name: NFKB inhibitor alpha), NFKB inhibitor alpha; IKKα (official name: CHUK), component of inhibitor of nuclear factor kappa B kinase complex; IKKβ (official name: IKBKB), inhibitor of nuclear factor kappa B kinase subunit beta; P, inorganic phosphate; p50 (official name: NFKB1), nuclear factor kappa B subunit 1; p65 (official name: RELA), RELA proto-oncogene, NF-kB subunit; TNF, tumor necrosis factor.