Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output.
Cell
; 183(1): 76-93.e22, 2020 10 01.
Article
en En
| MEDLINE
| ID: mdl-32931733
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
ATPasas de Translocación de Protón Mitocondriales
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ARN Circular
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Mitocondrias
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell
Año:
2020
Tipo del documento:
Article