PT  - JOURNAL ARTICLE
AU  - Singh, Aarti
AU  - Rigon, Manuel
AU  - Caldeira, Marta Gramaça
AU  - Faccenda, Danilo
AU  - Xia, Dong
AU  - Lopez-Tremoleda, Jordi
AU  - Al-Khateeb, Zahra Falah Hassan
AU  - Guo, Tong
AU  - Abeti, Rosella
AU  - Giunti, Paola
AU  - Campanella, Michelangelo
TI  - Mitochondria drive microglial NRLP3 inflammasome activation via TSPO
AID  - 10.1101/2024.03.18.585507
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.03.18.585507
4099  - http://biorxiv.org/content/early/2024/03/25/2024.03.18.585507.short
4100  - http://biorxiv.org/content/early/2024/03/25/2024.03.18.585507.full
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.