Depressed TFAM promotes acetaminophen-induced hepatotoxicity regulated by DDX3X-PGC1α-NRF2 signaling pathway.

Autor: Chen S; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China.; Department of Liver Oncology, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Cao Y; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Fan Z; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Xu L; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Pan Z; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Gao Y; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Wei L; The Second Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China., Wei Q; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China.; Department of Liver Oncology, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Tian Y; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Zhang X; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China., Liu M; Department of Liver Oncology, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. liumei@ccmu.edu.cn., Ren F; Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. renfeng7512@ccmu.edu.cn.
Jazyk: angličtina
Zdroj: Molecular medicine (Cambridge, Mass.) [Mol Med] 2024 Dec 19; Vol. 30 (1), pp. 246. Date of Electronic Publication: 2024 Dec 19.
DOI: 10.1186/s10020-024-01017-0
Abstrakt: Background: Acetaminophen (APAP)-induced acute liver injury (AILI) is the most prevalent cause of acute liver failure and mitochondrial dysfunction plays a dominant role in the pathogenesis of AILI. Mitochondrial transcription factor A (TFAM) is an important marker for maintaining mitochondrial functional homeostasis, but its functions in AILI are unclear. This study aimed to investigate the function of TFAM and its regulatory molecular mechanism in the progression of AILI.
Methods: The roles of TFAM and DEAD (Asp-Glu-Ala-Asp) box polypeptide 3 X-linked (DDX3X) in AILI were determined with TFAM overexpression and DDX3X knockdown, respectively.
Results: TFAM expression was suppressed in AILI patients. TFAM overexpression alleviated liver necrosis and mitochondrial dysfunction. Treatment of the AILI mice model with N-acetylcysteine (NAC), a drug used to treat APAP overdose, resulted in significant TFAM activation. In vivo experiments confirmed that TFAM expression was negatively regulated by DDX3X. Mechanistic studies showed that nuclear respiratory factor 2 (NRF-2), a key regulator of TFAM, was selectively activated after DDX3X knockdown via activated peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), in vivo and in vitro.
Conclusions: This study demonstrates that depressed hepatic TFAM plays a key role in the pathogenesis of AILI, which is regulated by the DDX3X-PGC1α-NRF2 signaling pathway.
Competing Interests: Declarations. Ethics approval and consent to participate: The content covered in this study was approved by the Ethics Committee in accordance with the requirements of local laws and regulations. All patients provided written informed consent before inclusion in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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