Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output

• Published in: Cell Vol. 183; no. 1; pp. 76 - 93.e22
• Main Authors: Zhao, Qiyi, Liu, Jiayu, Deng, Hong, Ma, Ruiying, Liao, Jian-You, Liang, Huixin, Hu, Jingxiong, Li, Jiaqian, Guo, Zhiyong, Cai, Junchao, Xu, Xiaoding, Gao, Zhiliang, Su, Shicheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2020
• Subjects: circular RNA; endoplasmic reticulum; fatty liver; fibroblasts; genome; insulin resistance; lipids; liver; mitochondria; therapeutics
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.08.009

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 mitochondrial 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-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α 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. [Display omitted] •Mitochondria-located circRNA SCAR inhibits mROS output and fibroblast activation•circRNA SCAR shuts down mPTP by binding to ATP5B•Lipid-induced ER stress impairs PGC-1α-mediated circRNA SCAR expression•Mitochondria-specific delivery of circRNA SCAR alleviates metaflammation in vivo A mitochondrial circRNA that is dysregulated in NAFLD patients’ liver fibroblasts directly binds and regulates the mitochondrial permeability transition pore to modulate mitochondrial metabolism and inflammation, providing a potential therapeutic angle.