Journal
CELL
Volume 183, Issue 1, Pages 76-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.08.009
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Funding
- National Key Research and Development Program of China [2017YFA0106300]
- Natural Science Foundation of China [91942309, 81971481, 81672614, 81870597, 81874226]
- National Science and Technology Major Project [2018ZX10302204]
- Natural Science Foundation of Guangdong Province [2016A030306023, 2017A030313878, 2018A030313769, 2018A050506033, 2019A1515011632]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515011632]
- Pearl River S&T Nova Programof Guangzhou [201710010083, 201710010048]
- Tiptop Scientific and Technical Innovative Youth Talents of Guangdong special support program [2016TQ03R553]
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Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondria! circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1 alpha, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1 ix by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet -induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.
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