RT Journal Article
SR Electronic
T1 Mitochondria drive microglial NRLP3 inflammasome activation via TSPO
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.03.18.585507
DO 10.1101/2024.03.18.585507
A1 Singh, Aarti
A1 Rigon, Manuel
A1 Caldeira, Marta Gramaça
A1 Faccenda, Danilo
A1 Xia, Dong
A1 Lopez-Tremoleda, Jordi
A1 Al-Khateeb, Zahra Falah Hassan
A1 Guo, Tong
A1 Abeti, Rosella
A1 Giunti, Paola
A1 Campanella, Michelangelo
YR 2024
UL http://biorxiv.org/content/early/2024/03/25/2024.03.18.585507.abstract
AB Uncontrolled microglial response is core to neuroinflammatory brain diseases. The correlation between the mitochondrial protein TSPO and inflammation has so far failed to explain whether TSPO positively or negatively regulates microglial function. The recent evidence on the species specificity of TSPO in microglia demands a deeper understanding of the protein biology in these brain-resident macrophages. To this end, we have here enrolled a murine model of microglial cells showing that TSPO is required for the priming of mitochondria to inflammation and a conduit for its escalation. Namely, in response to inflammatory cues TSPO is stabilised on the mitochondria where it binds and sequesters NOD-like receptor (NLR) protein (i), represses the PARK2-mediated mitophagy (ii) and engages the retrograde communication with the nucleus via the accumulation of the Nf-kB to promote the expression of pro-inflammatory genes (iii). Notably, the TSPO sustained inflammatory response drives cellular demise and ultimately leads to excitotoxicity (iv).Our findings advance the current knowledge of TSPO widening the understanding of mitochondria in inflammation and indicating a target for their regulation.Competing Interest StatementThe authors have declared no competing interest.