The research team directed by Prof. Shicheng Su from Sun Yat-sen Memorial Hospital revealed a new mechanism of liver immunometabolic inflammation regulated by a mitochondria-located circRNA

Immunometabolic diseases emerge as one of the biggest public health challenges due to the adoption of a high-calorie diet and sedentary lifestyle worldwide. Metaflammation is a hallmark of immunometabolic diseases, including nonalcoholic steatohepatitis (NASH), diabetes, and obesity. NASH is a progressive type of nonalcoholic fatty liver disease (NAFLD), which affects ~25% of the world population and is closely associated with other immunometabolic disorders, such as insulin resistance and hyperlipidemia. Therefore, to meet this important challenge of global health, there is a pressing need to elucidate how metabolic disorder is transited to uncontrollable inflammation. Recently, the research team directed by Prof.  Shicheng Su from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, revealed a new mechanism of liver immunometabolic inflammation regulated by a mitochondria-located circRNA. This work entitled "Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output" was published online in Cell on Sept. 14th, 2020. Prof. Shicheng Su from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Prof. Zhiliang Gao from The Third Affiliated Hospital, Sun Yat-sen University, and Prof. Xiaoding Xu from Sun Yat-sen Memorial Hospital, Sun Yat-sen University are the corresponding authors. Qiyi Zhao, an associate research fellow, Hond Deng, a chief physician, Jiayu Liu, an assistant research fellow, and Ruiying Ma, a postgraduate are co-first authors.

Here, by circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), the researchers observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, the researchers 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-1a, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1a 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. This is the first report to highlight the biological significance of mitochondria-located circRNAs. More importantly, this research demonstrated targeting mito-circRNAs can be a specific and restricted therapeutic strategy for immunometabolic disorders.

Collectively, Prof. Shicheng Su’s team uncovered the detailed molecular components of an ER-nucleus-mitochondria-cytosol communication pathway that drives lipid-mediated inflammation. They showed that targeting a disrupted inter-organelle metabolic axis by interfering mito-circRNAs provides an attractive therapeutic strategy for immunometabolic diseases.

Links to the article：https://doi.org/10.1016/j.cell.2020.08.009