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Mitochondrial Transplantation Reduces Injury and Improves Liver Function in a Porcine Model of Hepatic Ischemia/Reperfusion
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Christian Hobeika1, *Avinash N. Mukkala
2, *Kun Wang
3, *Nicola Pollmann
3, *Sujani Ganesh
3, *Francisco Calderon Novoa
3, *Catherine Parmentier
3, *Simon Qu
3, *Ramadan Karrout
2, *Cindy Lin
3, *Emma Mizdrak
3, *Mickaël Lesurtel
1, *Nazia Selzner
3, *Trevor Reichman
3, *Oyedele Adeyi
4, *Eno Hysi
2, Ori Rotstein
2, *Markus Selzner
31HPB Surgery and Liver transplantation, Beaujon Hospital, AP-HP, Université Paris-Cité, Clichy, France; 2Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada; 3Ajmera Transplant Centre, Toronto General Hospital, University Health Network, Toronto, ON, Canada; 4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
Objective: Mitochondrial dysfunction is a hallmark of liver ischemia/reperfusion (I/R). Organellar replacement by mitochondrial transplantation (MitoTx) represents a novel intervention to mitigate I/R injury. We hypothesized that MitoTx via portal vein infusion during reperfusion would be hepatoprotective in a survival porcine model of liver I/R.
Methods: Male Yorkshire pigs (38±1kg) were subjected to 2 hours of ischemia in the left hemi-liver (left portal-triad clamping), and at the beginning of reperfusion (marked as t=0h), animals were randomized to receive a 1-hour infusion of mitochondria (Mitos, 6.71x10
9/kg) or saline (controls) via the portal vein. The surgical team was blinded to treatment group. Mitos were autologous, isolated from
Rectus abdominis muscle (10g). Post isolation, Mitos viability was assured by membrane potential measurement using JC-1. Pigs’ recovery from anesthesia started at t=2h. Follow-up ended at t=24h. Blood and bile were collected from a venous line and a T-tube. Intraoperative liver tissue oxygen saturation (SO
2) was assessed by photoacoustic imaging. Two-way ANOVAs with Tukey’s tests were used, and hazard ratios (HR [95% CI]) were computed with Cox models. Mean±SE is reported.
Results: Twelve pigs (6 MitoTx vs. 6 controls) underwent 2-hour left hemi-liver I/R. All pigs recovered from anesthesia and were ambulatory at t=6h. MitoTx significantly reduced peak AST levels at t=2h reperfusion compared to control animals (300±47 vs. 879±255 U/L; p=0.049) (Fig. 1A). At t=24h, MitoTx pigs had lowered necrosis area percentage (4±2 vs. 17±7%, p=0.08) in left lobes, compared to controls I/R saline animals – all right lobes had 0% necrotic area. MitoTx pigs had shorter prothrombin time, plateauing around t=8h (12.9±0.3 vs. 14.1±0.1s; p=0.003), faster lactate clearance (<2 mmol/L) from the blood (HR: 1.3, [1.1, 1.7]; p=0.003) and from the bile (HR: 1.4, [1.1, 1.7]; p=0.009) compared to controls (Fig. 1B/C). Reperfusion triggered systemic inflammation (Fig. 1D); At t=6h, MitoTx pigs had decreased IL-6 (304±71 vs. 686±87 pg/mL; p=0.009) and a trend toward increased IL-10 at t=2h (22.1±7.7 vs. 6.4±4.4 pg/mL; p=0.113) in plasma, compared to controls. Photoacoustic imaging showed a reduction in O
2 saturation (SO
2) in the left lobe in both groups after clamping, with a better SO
2 recovery after clamp release in MitoTx pigs than in controls. Fluorescent imaging revealed that deep-red-labeled mitochondria were sequestered in the liver and kidney with no signal in the spleen or lungs (t=0-6h). At t=24h, no surgical complications or MitoTx-related adverse events were observed.
Conclusion: MitoTx via portal vein infusion reduces I/R injury, improves liver function, and lessens inflammation after prolonged porcine hemi-liver I/R. MitoTx can have important implications in clinical scenarios involving liver I/R, particularly in the context of liver transplantation with the emergence of donation after circulatory death and machine perfusion.
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