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

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

Cell (2020-09-16)
Qiyi Zhao, Jiayu Liu, Hong Deng, Ruiying Ma, Jian-You Liao, Huixin Liang, Jingxiong Hu, Jiaqian Li, Zhiyong Guo, Junchao Cai, Xiaoding Xu, Zhiliang Gao, Shicheng Su
ABSTRACT

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.

MATERIALS
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