Methyltransferase METTL1 Upregulates USF2 in a m7G-Dependent Manner to Accelerate Septic Cardiomyopathy by Inactivating PINK1/Parkin-Mediated Mitophagy.

Wei Dong, Jin Chen, Zhiping Xiong, Ruichun Liao, Junfei Weng, Zhichao Wang, Xiaoping Peng

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Article in Cardiovascular toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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7 authors.

Wei DongDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China.

Jin ChenDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China.

Zhiping XiongDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China.

Ruichun LiaoDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China.

Junfei WengDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China.

Zhichao WangDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China.

Xiaoping PengDepartment of Cardiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17 Yongwai Zheng Street, Nanchang, 330006, Jiangxi, China. ndyfy05769@ncu.edu.cn.

Funding

Natural Lipid Regulating Drug Confirmation Research Fund 2023-CAA-NLD-604The National Natural Science Foundation of China 82460374

6 · The paper itself

Abstract

Septic cardiomyopathy (SCM) is a severe complication of sepsis, characterized by high mortality. The activation of mitophagy in cardiomyocytes is crucial for alleviating SCM. The N7-methylguanosine (m7G) modification mediated by methyltransferase 1 (METTL1) is known to negatively regulate mitophagy. This study investigated the mechanism of METTL1 in the mitophagy of cardiomyocytes in SCM. Human cardiomyocytes (HCMs) were stimulated with lipopolysaccharide (LPS) to establish the SCM model. C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to create a septic model. Mitophagy was assessed utilizing the mt-Keima assay, while mitochondrial membrane potential was measured with the JC-1 assay. MitoSOX Red assay was employed to evaluate levels of mitochondrial reactive oxygen species (ROS). The interaction between METTL1 and upstream transcription factor 2 (USF2), as well as between USF2 and PTEN-induced putative kinase protein 1 (PINK1), was confirmed through RNA immunoprecipitation (RIP) and RNA pull-down or dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The silenced METTL1 mitigated LPS-triggered myocardial damage in vitro. The inhibition of mitophagy nullified the protective effects conferred by METTL1 silencing in LPS-induced HCMs. Consistently, METTL1 silencing ameliorated myocardial injury induced by sepsis in a mouse model. METTL1 enhanced the expression of USF2 in an m7G-dependent manner. USF2, in turn, inactivated the PINK1/Parkin signaling pathway by repressing PINK1 transcription. The repression of USF2 negated the protective effects of METTL1 silencing on myocardial damage and mitophagy. METTL1 aggravated myocardial injury by inhibiting PINK1/Parkin-mediated mitophagy through the upregulation of USF2 in a m7G-dependent manner in SCM models, thereby identifying METTL1 as a potential therapeutic target for SCM.

Indexed as

CardiomyopathiesMethyltransferasesMitochondria, HeartMitophagyMyocytes, CardiacProtein KinasesSepsisUbiquitin-Protein LigasesUpstream Stimulatory FactorsAnimalsCells, CulturedDisease Models, AnimalEpitranscriptomeHumansMaleMembrane Potential, MitochondrialMethyltransferasesparkin proteinProtein KinasesPTEN-Induced Putative KinaseUbiquitin-Protein LigasesUpstream Stimulatory FactorsMETTL1MitophagyPINK1/ParkinSCMUSF2

Identifiers

PMID42490034

DOI10.1016/j.virs.2025.05.007

What OpenQuestion holds

Textmetadata

Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.