Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prognostic impact of excessive mitochondrial fission in patients with heart failure and evaluation of mitochondrial dynamics-related miRNAs in heart failure

Hypertension Research (2025)Cite this article

Abstract

Mitochondria are dynamic organelles that can change their morphology. The role of these mitochondrial dynamics in cardiomyocytes remains obscure in patients with heart failure (HF). Endomyocardial biopsies were performed consecutively in 127 HF patients, and mitochondrial morphology data were obtained from 111 patients by electron microscopy. The patients were divided into three groups according to mitochondrial area quartiles (fission [Q1, area ≤ 0.119 μm2, n = 27], normal [Q2/Q3, 0.120 μm2 ≤ area ≤ 0.178 μm2, n = 55], and fusion [Q4, area ≥ 0.179 μm2, n = 28]). In the fission group, the serum N-terminal pro-brain natriuretic peptide and B-type natriuretic peptide (BNP) levels were significantly higher, and patients with HF and a reduced left ventricular ejection fraction were more common, than in the other groups. A multivariate logistic regression model showed that diabetes mellitus was independently associated with placement in the fission group (odds ratio: 2.835, 95%confidence interval [CI]: 1.037–7.752). A Kaplan–Meier curve analysis showed that the prognosis was significantly poorer in the fission group than in the other groups, and a multivariate Cox regression model revealed fission to be an independent predictor of 1500-day mortality (hazard ratio: 4.365, 95%CI: 1.198–15.909). The circulating levels of miR-140-5p (≥2500) were independently associated with the presence of mitochondrial fission (OR: 3.622, 95%CI: 1.260–10.413). Excessive mitochondrial fission was observed in patients with severe HF status, and was independently associated with adverse outcomes in HF patients. Circulating mitochondrial dynamics-related miRNA levels might be of use in detecting mitochondrial fission in the cardiomyocytes of HF patients.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The deidentified participant data will not be shared.

References

  1. Sakata Y, Shimokawa H. Epidemiology of heart failure in Asia. Circ J. 2013;77:2209–17.

    Article  PubMed  Google Scholar 

  2. Shimokawa H, Miura M, Nochioka K, Sakata Y. Heart failure as a general pandemic in Asia. Eur J Heart Fail. 2015;17:884–92. https://doi.org/10.1002/ejhf.319.

    Article  PubMed  Google Scholar 

  3. Shirakabe A, Asai K, Hata N, Yokoyama S, Shinada T, Kobayashi N, et al. Clinical significance of matrix metalloproteinase (MMP)-2 in patients with acute heart failure. Int Heart J. 2010;51:404–10. https://doi.org/10.1536/ihj.51.404.

    Article  PubMed  CAS  Google Scholar 

  4. Shirakabe A, Hata N, Kobayashi N, Shinada T, Tomita K, Tsurumi M, et al. Prognostic impact of acute kidney injury in patients with acute decompensated heart failure. Circ J. 2013;77:687–96. https://doi.org/10.1253/circj.cj-12-0994.

    Article  PubMed  CAS  Google Scholar 

  5. Shirakabe A, Okazaki H, Matsushita M, Shibata Y, Shigihara S, Nishigoori S, et al. Type III procollagen peptide level can indicate liver dysfunction associated with volume overload in acute heart failure. ESC Heart Fail. 2022;9:1832–43. https://doi.org/10.1002/ehf2.13878.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sawatani T, Shirakabe A, Okazaki H, Matsushita M, Shibata Y, Shigihara S, et al. Clinical significance of the N-terminal pro-brain natriuretic peptide and B-type natriuretic peptide ratio in the acute phase of acute heart failure. Eur Heart J Acute Cardiovasc Care. 2021;10:1016–26. https://doi.org/10.1093/ehjacc/zuab068.

    Article  PubMed  Google Scholar 

  7. Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S, Toli J, et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. 2015;116:264–78. https://doi.org/10.1161/CIRCRESAHA.116.303356.

    Article  PubMed  CAS  Google Scholar 

  8. Ikeda Y, Shirakabe A, Brady C, Zablocki D, Ohishi M, Sadoshima J. Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system. J Mol Cell Cardiol. 2015;78:116–22. https://doi.org/10.1016/j.yjmcc.2014.09.019.

    Article  PubMed  CAS  Google Scholar 

  9. Ikeda Y, Sciarretta S, Nagarajan N, Rubattu S, Volpe M, Frati G, et al. New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart. Oxid Med Cell Longev. 2014;2014:210934. https://doi.org/10.1155/2014/210934.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Iwatani N, Kubota K, Ikeda Y, Tokushige A, Miyanaga S, Higo K, et al. Different characteristics of mitochondrial dynamics-related miRNAs on the hemodynamics of pulmonary artery hypertension and chronic thromboembolic pulmonary hypertension. J Cardiol. 2021;78:24–30. https://doi.org/10.1016/j.jjcc.2021.03.008.

    Article  PubMed  Google Scholar 

  11. Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, et al. JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure- Digest Version. Circ J. 2019;83:2084–184. https://doi.org/10.1253/circj.CJ-19-0342.

    Article  PubMed  Google Scholar 

  12. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891–975. https://doi.org/10.1002/ejhf.592.

    Article  PubMed  Google Scholar 

  13. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726. https://doi.org/10.1093/eurheartj/ehab368.

    Article  PubMed  CAS  Google Scholar 

  14. Sasaki Y, Ikeda Y, Uchikado Y, Akasaki Y, Sadoshima J, Ohishi M. Estrogen plays a crucial role in Rab9-dependent mitochondrial autophagy, delaying arterial senescence. J Am Heart Assoc. 2021;10:e019310. https://doi.org/10.1161/JAHA.120.019310.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gu D, Zou X, Ju G, Zhang G, Bao E, Zhu Y. Mesenchymal stromal cells derived extracellular vesicles ameliorate acute renal ischemia reperfusion injury by inhibition of mitochondrial fission through miR-30. Stem Cells Int. 2016;2016:2093940. https://doi.org/10.1155/2016/2093940.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Li J, Li Y, Jiao J, Wang J, Qin D, Li P. Mitofusin 1 is negatively regulated by microRNA 140 in cardiomyocyte apoptosis. Mol Cell Biol. 2014;34:1788–99. https://doi.org/10.1128/MCB.00774-13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Zhao Y, Ponnusamy M, Liu C, Tian J, Dong Y, Gao J, et al. MiR-485-5p modulates mitochondrial fission through targeting mitochondrial anchored protein ligase in cardiac hypertrophy. Biochim Biophys Acta Mol Basis Dis. 2017;1863:2871–81. https://doi.org/10.1016/j.bbadis.2017.07.034.

    Article  PubMed  CAS  Google Scholar 

  18. Wang JX, Jiao JQ, Li Q, Long B, Wang K, Liu JP, et al. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med. 2011;17:71–78. https://doi.org/10.1038/nm.2282.

    Article  PubMed  CAS  Google Scholar 

  19. Uchikado Y, Ikeda Y, Ohishi M. Current understanding of the pivotal role of mitochondrial dynamics in cardiovascular diseases and senescence. Front Cardiovasc Med. 2022;9:905072. https://doi.org/10.3389/fcvm.2022.905072.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Shirakabe A, Zhai P, Ikeda Y, Saito T, Maejima Y, Hsu CP, et al. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation. 2016;133:1249–63. https://doi.org/10.1161/CIRCULATIONAHA.115.020502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Din S, Mason M, Völkers M, Johnson B, Cottage CT, Wang Z, et al. Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation. Proc Natl Acad Sci USA 2013;110:5969–74. https://doi.org/10.1073/pnas.1213294110.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, et al. Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res. 2012;110:1484–97. https://doi.org/10.1161/CIRCRESAHA.111.263848.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ong SB, Hall AR, Hausenloy DJ. Mitochondrial dynamics in cardiovascular health and disease. Antioxid Redox Signal. 2013;19:400–14. https://doi.org/10.1089/ars.2012.4777.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Yoon Y, Galloway CA, Jhun BS, Yu T. Mitochondrial dynamics in diabetes. Antioxid Redox Signal. 2011;14:439–57. https://doi.org/10.1089/ars.2010.3286.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Iheagwam FN, Joseph AJ, Adedoyin ED, Iheagwam OT, Ejoh SA. Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight. Pathophysiology 2025;32. https://doi.org/10.3390/pathophysiology32010009.

  26. Wei L, Fang C, Jiang Y, Zhang H, Gao P, Zhou X, et al. The role of placental MFF-mediated mitochondrial fission in gestational Diabetes Mellitus. Diabetes Metab Syndr Obes. 2025;18:541–54. https://doi.org/10.2147/DMSO.S484002.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Abercrombie DM, Kanmera T, Angal S, Tamaoki H, Chaiken IM. Cooperative interactions in neurophysin-neuropeptide hormone complexes. Analytical affinity chromatography of native and covalently-modified neurophysins. Int J Pept Protein Res. 1984;24:218–32.

    Article  PubMed  CAS  Google Scholar 

  28. Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol. 1997;47:287–96. https://doi.org/10.1046/j.1365-2265.1997.2361058.x.

    Article  CAS  Google Scholar 

  29. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation. 2010;122:900–9. https://doi.org/10.1161/CIRCULATIONAHA.109.924167.

    Article  PubMed  Google Scholar 

  30. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J. 2007;28:3076–93. https://doi.org/10.1093/eurheartj/ehm456.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the staff of Kagoshima University and Nippon Medical School Chiba Hokusoh Hospital for collecting the medical data. We would like to thank Uni-edit (https://uni-edit.net/) for editing and proofreading this manuscript.

Funding

This research received Grants-in-Aid for Scientific Research grants from the Ministry of Health, Labor and Welfare in Japan. This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Division of Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan

    Akihiro Shirakabe, Masato Matsushita, Tomofumi Sawatani, Shota Shigihara, Kenichi Tani, Masaki Morooka & Masahito Takahashi

  2. Department of Cardiovascular Medicine, National Hospital Organization, Minami Kyushu Hospital, Kagoshima, Japan

    Yoshiyuki Ikeda

  3. Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan

    Yoshiyuki Ikeda, Yoshihiro Uchikado & Mitsuru Ohishi

  4. Cardiovascular Center, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan

    Masato Matsushita, Masaki Morooka & Nobuaki Kobayashi

  5. Department of Cell Biology and Molecular Medicine, Rutgers–New Jersey Medical School, Newark, USA

    Masato Matsushita & Junichi Sadoshima

  6. Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan

    Kuniya Asai

Authors
  1. Akihiro Shirakabe
    View author publications

    Search author on:PubMed Google Scholar

  2. Yoshiyuki Ikeda
    View author publications

    Search author on:PubMed Google Scholar

  3. Yoshihiro Uchikado
    View author publications

    Search author on:PubMed Google Scholar

  4. Masato Matsushita
    View author publications

    Search author on:PubMed Google Scholar

  5. Tomofumi Sawatani
    View author publications

    Search author on:PubMed Google Scholar

  6. Shota Shigihara
    View author publications

    Search author on:PubMed Google Scholar

  7. Kenichi Tani
    View author publications

    Search author on:PubMed Google Scholar

  8. Masaki Morooka
    View author publications

    Search author on:PubMed Google Scholar

  9. Masahito Takahashi
    View author publications

    Search author on:PubMed Google Scholar

  10. Nobuaki Kobayashi
    View author publications

    Search author on:PubMed Google Scholar

  11. Mitsuru Ohishi
    View author publications

    Search author on:PubMed Google Scholar

  12. Junichi Sadoshima
    View author publications

    Search author on:PubMed Google Scholar

  13. Kuniya Asai
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Akihiro Shirakabe.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shirakabe, A., Ikeda, Y., Uchikado, Y. et al. Prognostic impact of excessive mitochondrial fission in patients with heart failure and evaluation of mitochondrial dynamics-related miRNAs in heart failure. Hypertens Res (2025). https://doi.org/10.1038/s41440-025-02338-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41440-025-02338-1

Keywords

Search

Advanced search

Quick links