Mitochondrial cristae architecture protects against mtDNA release and inflammation

• Published in: Cell reports (Cambridge) Vol. 41; no. 10; p. 111774
• Main Authors: He, Baiyu, Yu, Huatong, Liu, Shanshan, Wan, Huayun, Fu, Song, Liu, Siqi, Yang, Jun, Zhang, Zihan, Huang, Huanwei, Li, Qi, Wang, Fengchao, Jiang, Zhaodi, Liu, Qinghua, Jiang, Hui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.12.2022
• Subjects: Animals; cGAS-STING; cristae architecture; DNA, Mitochondrial - genetics; Humans; inflammation; Metaxin2; Mice; MICOS; mtDNA release; OPA1; SAM; type I interferon response; OPA1; MICOS; CP: Cell biology; inflammation; cristae architecture; mtDNA release; CP: Molecular biology; Metaxin2; cGAS-STING; type I interferon response; SAM
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111774

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, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the F1Fo-ATP 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 mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases. [Display omitted] •A mitochondria-targeted sgRNA library for interrogating mitochondrial function•Mitochondrial regulators of type I interferon (IFN-I) response are identified•Cristae disorganization induces mtDNA release and STING-dependent IFN-I response•Knockout of cristae regulator Metaxin-2 causes the IFN-I response in vivo Via a mitochondria-targeted CRISPR knockout screen, He et al. find that mitochondrial cristae disorganization causes mtDNA release and activates the type I interferon response via the cGAS-STING pathway, linking mitochondrial ultrastructural abnormality with inflammation.