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

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.