Mitochondrial cristae architecture protects against mtDNA release and inflammation

Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune-and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochon-drial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the F1FoATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochon-drial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degener-ative diseases.

Automated summary

This study reveals the crucial role of cristae architecture in preventing mtDNA release and inflammation. The disruption of cristae organizers leads to mtDNA release and the immune response. These findings provide mechanistic insights into the link between mitochondrial cristae disorganization and inflammation, which are emerging hallmarks of aging and age-related degenerative diseases.