Mitochondrial Transplantation Reduces Injury and Improves Liver Function in a Porcine Model of Hemi-hepatic Ischemia/Reperfusion

Abstract

Objective: To assess mitochondrial transplantation (MitoTx) via portal vein infusion to reduce liver ischemia-reperfusion injury (I/R) in a survival porcine model.

Summary background data: MitoTx has been shown to alleviate I/R injury in various organs.

Methods: Male Yorkshire pigs (38±1 kg) 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=0 h), animals received a 1-hour infusion of autologous mitochondria (MT, 7×10^9/kg) or saline (controls) via the portal vein. Liver tissue oxygen saturation (sO 2 ) was assessed by photoacoustic imaging.

Results: Twelve pigs (6 MitoTx vs. 6 controls) underwent 2-hour left hemi-liver I/R. All pigs recovered and were ambulatory at t=6 hours. MitoTx reduced peak AST levels at t=2 hours compared with controls (299.83±46.62 vs. 878.83±255.09 UI/L; P =0.049). At t=24 hours, MitoTx pigs had lowered necrosis area percentage (8.01±4.12 vs. 23.40±7.33 %; P =0.08) in left livers-all right lobes had 0% necrotic area. MitoTx pigs had shorter prothrombin time, plateauing around t=8 hours (12.9±0.3 vs. 14.1±0.1 s; 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 with controls. At t=6 hours, MitoTx pigs had decreased IL-6 (304±71 vs. 686±87 pg/mL; P =0.007). Photoacoustic imaging showed that MitoTx pigs had a better recovery of sO 2 from baseline in left livers compared with controls (at t=30 min; -3.05±2.72 vs. -15.19±2.92 %; P =0.016).

Conclusion: MitoTx reduces injury and improves liver function after prolonged liver I/R, showing promise for liver transplantation.

Keywords: inflammation; large animal study; liver function; mitochondrial transplantation; porcine liver ischemia/reperfusion injury.