Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury

Avinash Naraiah Mukkala^{1

2}, Bruna Araujo David^{3

4}, Menachem Ailenberg¹, Jady Liang^{1

5}, Chirag Manoj Vaswani^{1

5}, Danielle Karakas^{1

6}, Rachel Goldfarb¹, William Barbour¹, Avishai Gasner¹, Ruoxian Scarlet Wu¹, Raluca Petrut¹, Mirjana Jerkic¹, Ana Cristina Andreazza⁷, Claudia Dos Santos^{1

8}, Heyu Ni^{1

5

6

9}, Haibo Zhang^{1

5

8

10}, Andras Kapus^{1

11}, Paul Kubes^{3

4}, Ori David Rotstein^{1

2

12

13}

Affiliations

¹ Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
³ Department of Physiology and Pharmacology, University of Calgary; Calgary, AB, Canada.
⁴ Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary; Calgary, AB, Canada.
⁵ Department of Physiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁷ Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁸ Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁹ Canadian Blood Services Centre for Innovation, Canadian Blood Service; Toronto, ON, Canada.
¹⁰ Department of Anesthesiology and Pain Medicine, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
¹¹ Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
¹² Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada.
¹³ Department of Surgery, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.

PMID: 39912224
DOI: 10.1097/SLA.0000000000006655

Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury

Avinash Naraiah Mukkala et al. Ann Surg. 2025.

. 2025 Jun 1;281(6):1032-1047.

doi: 10.1097/SLA.0000000000006655. Epub 2025 Feb 6.

Authors

Affiliations

¹ Keenan Research Centre for Biomedical Science, Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
³ Department of Physiology and Pharmacology, University of Calgary; Calgary, AB, Canada.
⁴ Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary; Calgary, AB, Canada.
⁵ Department of Physiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁷ Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁸ Interdepartmental Division of Critical Care, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
⁹ Canadian Blood Services Centre for Innovation, Canadian Blood Service; Toronto, ON, Canada.
¹⁰ Department of Anesthesiology and Pain Medicine, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
¹¹ Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.
¹² Department of Surgery, St. Michael's Hospital, Unity Health Toronto; Toronto, ON, Canada.
¹³ Department of Surgery, Temerty Faculty of Medicine, University of Toronto; Toronto, ON, Canada.

PMID: 39912224
DOI: 10.1097/SLA.0000000000006655

Abstract

Objective: To investigate the hepatoprotective effects of mitochondrial transplantation (MTx) in a murine liver ischemia/reperfusion (I/R) model.

Background: Sequential liver ischemia, followed by reperfusion (I/R), is a pathophysiological process underlying hepatocellular injury in a number of clinical contexts, such as hemorrhagic shock/resuscitation, major elective liver surgery, and organ transplantation. A unifying pathogenic consequence of I/R is mitochondrial dysfunction. Restoration of mitochondria through transplantation (MTx) has emerged as a potential therapeutic in I/R. However, its role in liver I/R and its mechanisms of action remain poorly defined.

Methods: We investigated the hepatoprotective effects of MTx in an in vivo mouse model of liver I/R and used in vivo imaging and various knockout and transgenic mouse models to determine the mechanism of protection.

Results: We found that I/R-induced hepatocellular injury was prevented by MTx, as measured by plasma ALT, AST, and liver histology. In addition, I/R-induced pro-inflammatory cytokine release (IL-6, TNFα) was dampened by MTx, and anti-inflammatory IL-10 was enhanced. Moreover, MTx lowered neutrophil infiltration into both the liver sinusoids and lung bronchoalveolar lavage fluid, suggesting a local and distant reduction in inflammation. Using in vivo intravital imaging, we found that I/R-subjected Kupffer cells (KCs), rapidly sequestered transplanted mitochondria, and acidified mitochondria within lysosomal compartments. To specifically interrogate the role of KCs, we depleted KCs using the diphtheria toxin-inducible Clec4f/iDTR transgenic mouse, then induced I/R, and discovered that KCs are necessary for the beneficial effects of MTx. Finally, we induced I/R in the complement receptor of the immunoglobulin (CRIg) superfamily knockout mice and found that CRIg was required for mitochondria capture by KCs and mitochondria-mediated hepatoprotection.

Conclusions: In this study, we demonstrated that CRIg-dependent capture of mitochondria by I/R-subjected KCs is a hepatoprotective mechanism in vivo . These data progress knowledge on the mechanisms of MTx and open new avenues for clinical translation.

Keywords: CRIg; Kupffer cell; inflammation; liver ischemia/reperfusion injury; mitochondria.

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Conflict of interest statement

The authors report no conflicts of interest.

References

1. Abu-Amara M, Yang SY, Tapuria N, et al. Liver ischemia/reperfusion injury: Processes in inflammatory networks—a review. Liver Transpl. 2010;16:1016–1032.
1. Karmaniolou II, Theodoraki KA, Orfanos NF, et al. Resuscitation after hemorrhagic shock: the effect on the liver—a review of experimental data. J Anesth. 2013;27:447–460.
1. Wu MY, Yiang GT, Liao WT, et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 2018;46:1650–1667.
1. Zhang H, Yan Q, Wang X, et al. The role of mitochondria in liver ischemia-reperfusion injury: from aspects of mitochondrial oxidative stress, mitochondrial fission, mitochondrial membrane permeable transport pore formation, mitophagy, and mitochondria-related protective measures. Oxid Med Cell Longev. 2021;2021:6670579.
1. Wang L, Feng ZJ, Ma X, et al. Mitochondrial quality control in hepatic ischemia-reperfusion injury. Heliyon. 2023;9:e17702.

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Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury

Affiliations

Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

LinkOut - more resources

Full Text Sources

Miscellaneous