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Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response

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Abstract

Background

Sepsis-induced myocardial dysfunction is associated with worse clinical outcomes and high mortality, but no effective therapeutic intervention has been explored, reinforcing the urgent need to develop innovative strategies. Mitochondrial dysfunction underlies the pathogenesis of sepsis-induced myocardial dysfunction. Herein, we assessed the effect of mitochondrial transplantation on sepsis-induced myocardial dysfunction in a rat model of cecal ligation and puncture (CLP)-induced sepsis.

Methods

Male Wistar rats (n = 80, 12 weeks old, 250-300 g) were divided into groups with/without CLP-induced sepsis receiving mitochondrial transplantation in single or two repetitive injections (1 h or 1 and 7 h post-CLP, respectively). Mitochondria were isolated from donor rats and injected intravenously (400 µl of mitochondrial suspension containing 7.5 × 106 mitochondria/ml of respiration buffer) in recipient groups. Twenty-four hours post-operation, LDH and cTn-I levels, mitochondrial functional endpoints, expression of mitochondrial biogenesis (SIRT-1 and PGC-1α) and fission/fusion (Drp1/Mfn1 and Mfn2) genes, and inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels were evaluated. Survival was tested over 72 h post-operation.

Results

Mitotherapy significantly improved 72-hours survival (P < .05) and decreased LDH and cTn-I levels (P < .01). It also restored mitochondrial function and expression of mitochondrial biogenesis and fusion genes, and decreased the expression of mitochondrial fission gene and the levels of inflammatory cytokines (P < .05 to P < .01). Mitotherapy with repetitive injections at 1 and 7 h post-CLP provided noticeable mitoprotection in comparison with the group receiving mitotherapy at single injection.

Conclusion

Mitotherapy improved mitochondrial function, biogenesis, and dynamic associated with SIRT-1/PGC-1α network and suppressed inflammatory response in CLP-induced sepsis model, therefore, offers a promising strategy to overcome life-threatening sepsis challenge.

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Availability of data and materials

The datasets used during the present work are available from the corresponding authors on reasonable request.

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Acknowledgements

The authors appreciate the help of Dr. Soleyman Bafadam (PhD student of Medical Physiology at Tabriz University of Medical Sciences) in animal handling.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study has been supported by Drug Applied Research Center at Tabriz University of Medical Sciences, Tabriz-Iran.

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Authors and Affiliations

  1. Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Behnaz Mokhtari

  2. Anesthesiology Department, Ali Nasab Hospital, Tabriz, Iran

    Masoud Hamidi

  3. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Badalzadeh

  4. Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Behnaz Mokhtari & Reza Badalzadeh

  5. Evidence-based Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Ata Mahmoodpoor

Authors
  1. Behnaz Mokhtari
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  2. Masoud Hamidi
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  4. Ata Mahmoodpoor
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Contributions

B.M. performed the experimental tests, gathered and analyzed the data, and wrote the manuscript. M.H. contributed to the experimental tests. R.B. and A.M. did the study design and supervised the whole project. B.M. and R.B. critically revised and finalized the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Reza Badalzadeh or Ata Mahmoodpoor.

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Conflict of interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

All experimental protocols and procedures were approved by the Institutional Animal Ethical Committee at the Faculty of Medicine of Tabriz University of Medical Sciences (Ethics approval number: IR.TBZMED.VCR.REC.1399.114).

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Mokhtari, B., Hamidi, M., Badalzadeh, R. et al. Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response. Mol Biol Rep 50, 2147–2158 (2023). https://doi.org/10.1007/s11033-022-08115-4

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  • DOI: https://doi.org/10.1007/s11033-022-08115-4

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