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Hepatology
Original research
Novel function of MOTS-c in mitochondrial remodelling contributes to its antiviral role during HBV infection
  1. Caorui Lin1,2,
  2. Linjie Luo1,2,
  3. Zhen Xun1,2,
  4. Chenggong Zhu1,2,
  5. Ying Huang1,2,
  6. Yuchen Ye1,2,
  7. Jiawei Zhang1,2,
  8. Tianbin Chen1,2,
  9. Songhang Wu1,2,
  10. Fuguo Zhan1,2,
  11. Bin Yang1,2,
  12. Can Liu1,2,
  13. Ning Ran3,
  14. Qishui Ou1,2
  1. 1 Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
  2. 2 Department of Laboratory Medicine, National Reginal Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
  3. 3 Institute of Medical Sciences, The Second Hospital & Orthopedic Research Center of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  1. Correspondence to Dr Qishui Ou, Fujian Medical University, Fuzhou, Fujian, China; ouqishui{at}fjmu.edu.cn; Dr Ning Ran; NingRan{at}sdu.edu.cn; Dr Can Liu; liucan{at}fjmu.edu.cn

Abstract

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.

https://doi.org/10.1136/gutjnl-2023-330389

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.