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Fig. 4 | Acta Neuropathologica Communications

Fig. 4

From: PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Fig. 4

PINK1/PARKIN-signalling and inflammation. Mice lacking Parkin or Pink1 upon acute (exhaustive exercise-induced) or chronic (mitochondrial DNA (mtDNA) mutation-induced) mitochondrial stress present inflammation due to the activation of the stimulator of interferon genes (STING) as result from the accumulation of mtDNA mutations and release of mtDNA into the cytosol. While, in systemic lupus erythematosus excessive IFNα damages mitochondrial respiration, leading to oxidative stress that impairs lysosomal degradation and obstructs autophagic clearance. Undegraded mtDNA from mitochondria, interact with the cytosolic DNA sensor cGAS in a sequence-independent way, promoting a conformational change of cGAS to catalyse the formation of 2,3-cyclic GMP-AMP (cGAMP). The cGAS activation, as well as cGAMP synthase, activate STING, recruiting binding kinase 1 (TBK1) as well as interferon regulatory factor 3 (IRF3). The IRF3 then displaces to the nucleus and induces immune-stimulated genes and type I IFN expression. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling can also be activated by STING. In the absence of PARKIN and PINK1, high levels of mitochondrial antigens are presented to major histocompatibility complex (MHC) class I molecules in macrophages and dendritic cells triggering an adaptive immune response

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