Objective Hepatitis B virus (HBV) infection causes substantial harm to mitochondrial activity, which hinders the development of effective treatments for chronic hepatitis B (CHB). The discovery of the mitochondrial-derived short peptide MOTS-c, which possesses multiple bioactivities, offers a promising new approach in treating HBV infection. This study aims to explore the diagnostic and therapeutic potential of MOTS-c in HBV-related diseases and its molecular mechanism.
Design In total, 85 healthy subjects and 404 patients with HBV infection, including 20 clinical treatment cohorts, were recruited for this study. MOTS-c levels were measured by ELISA and its diagnostic value was evaluated by receiving operating characteristic curve analysis. The therapeutic effect of MOTS-c was observed in multiple HBV-infected mice and cells through various techniques, including transcriptomic sequencing, flow cytometry, immunofluorescence and electron microscopy. Additionally, MOTS-c’s potential interaction with myosin-9 (MYH9) and actin was predicted using immunoprecipitation, proteomics and target prediction software.
Results MOTS-c negatively correlates with HBV DNA expression (R=−0.71), and its AUC (the area under the curve) for distinguishing CHB from healthy controls is 0.9530, and IA (immune reactive) from IC (inactive HBV carrier) is 0.8689. Inhibition of HBV replication (with a 50–70% inhibition rate) was observed alongside improved liver function without notable toxicity in vitro or in vivo. MOTS-c was found to promote mitochondrial biogenesis and enhance the MAVS (mitochondrial antiviral signalling protein) signalling pathway. The impact is dependent on MOTS-c’s ability to regulate MYH9-actin-mediated mitochondrial homeostasis.
Conclusion MOTS-c has the potential to serve as a biomarker for the progression of HBV infection while also enhancing antiviral efficacy. These findings present a promising innovative approach for effectively treating patients with CHB. Furthermore, our research uncovers a novel role for MOTS-c in regulating MYH9-actin-mediated mitochondrial dynamics and contributing to mitochondrial biogenesis.
- hepatitis B
- chronic viral hepatitis
- diagnostic virology
- antiviral therapy
Data availability statement
Data are available upon reasonable request.
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CL, LL and ZX contributed equally.
Contributors QO is responsible for the overall content as the guarantor. CaoL and QO conceived the study questions and designed the study. CaoL, LL, NR and ZX performed the experiments and analyses. CZ, YY and YH collected samples and laboratory data. JZ, TC, SW, CanL, BY and QO provided materials. CaoL drafted the manuscript. QO, CanL and NR supervised the study. All authors contributed to the article and approved the submitted version.
Funding This work was supported by the National Natural Science Foundation of China (Grant number 82202597, 82030063, 82102560), the Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number 2021Y9087), Natural Science Foundation of Fujian Province (Grant number 2022J05051), and Fujian Provincial Health Technology Project (Grant number 2020GGA041).
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
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