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bioRxiv · 10.1101/2024.09.04.608457

Mitochondrial transplantation: a novel therapy for liver ischemia/reperfusion injury

Mukkala, A. N.·David, B. A.·Ailenberg, M.·Liang, J.·Vaswani, C. M.·Karakas, D.·Goldfarb, R.·Barbour, W.·Gasner, A.·Wu, R. S.·Petrut, R.·Jerkic, M.·Andreazza, A.·dos Santos, C.·Ni, H.·Zhang, H.·Kapus, A.·Kubes, P.·Rotstein, O.
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Abstract

MINI-ABSTRACTMitochondrial transplantation prevented liver ischemia/reperfusion-induced hepatocellular injury and inflammation. In vivo intravital microscopy demonstrated that liver resident macrophages, namely Kupffer cells, rapidly sequestered, internalized and acidified transplanted mitochondria through the CRIg immunoreceptor. Mechanistically, both Kupffer cells and CRIg were necessary for the hepatoprotective and anti-inflammatory effects of mitochondrial transplantation. STRUCTURED ABSTRACTO_ST_ABSObjectiveC_ST_ABSTo investigate the hepatoprotective effects of mitochondrial transplantation in a murine liver ischemia/reperfusion (I/R) model. Summary background dataSequential 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 via transplantation (MTx) has emerged as potential therapeutic in I/R. However, its role in liver I/R and its mechanisms of action remain poorly defined. MethodsWe 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. ResultsWe found that I/R-induced hepatocellular injury was prevented by MTx, as measured by plasma ALT, AST and liver histology. Additionally, I/R-induced pro-inflammatory cytokine release (IL-6, TNF) was dampened by MTx, and anti-inflammatory IL-10 was enhanced. Moreover, MTx lowered neutrophil infiltration into both the liver sinusoids and lung BALF, 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 complement receptor of the immunoglobulin superfamily (CRIg) knockout mice and found that CRIg was required for mitochondria capture by KCs and mitochondrial-mediated hepatoprotection. ConclusionsIn this study, we demonstrated that CRIg-dependent capture of mitochondria by I/R-subjected Kupffer cells is a hepatoprotective mechanism in vivo. These data progress knowledge on the mechanisms of MTx and opens new avenues for clinical translation.

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Mukkala, A. N., David, B. A., Ailenberg, M., Liang, J., Vaswani, C. M., Karakas, D., Goldfarb, R., Barbour, W., Gasner, A., Wu, R. S., Petrut, R., Jerkic, M., Andreazza, A., dos Santos, C., Ni, H., Zhang, H., Kapus, A., Kubes, P., Rotstein, O.. 2024-09-05. Mitochondrial transplantation: a novel therapy for liver ischemia/reperfusion injury. https://doi.org/10.1101/2024.09.04.608457

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