Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation

Abstract

Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = −1.0, 95% CI: (−2.3, 0.3) and MD = −1.1, 95% CI: (−3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = −1.8, 95% CI: (−2.9, −0.7) and MD = −2.1 MD; CI: (−4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function.

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach

“…Consequently, this calls for an exploration of the underlying protective mechanisms by which PEG35 confers mitochondrial protection on fatty liver grafts preserved in IGL-1 and IGL-2 solutions whose mechanisms substantially differ from the ones induced in HOPE [31], where the transient oxygenation during hypothermic preservation is responsible for maintaining mitochondrial activity function at basal levels. This confirms the relevance of organ preservation strategies on the mitochondrial status and their subsequent benefits in liver transplantation, as recently published by Horvath et al [32].…”

Cerium oxide nanoparticles administration during machine perfusion of discarded human livers: A pilot study

“…[ 33,34 ] Mitochondrial damage may impair the electron flow and promote the mitochondrial Ca 2+ flux and ROS production that damage mitochondrial membrane lipids, increasing mitochondrial membrane permeability along with Ca 2+ ‐induced mitochondrial swelling. [ 32 ] EM‐based ultrastructural analysis demonstrated mitochondrial swelling with alterations of mitochondrial matrix and cristae and the presence of GM in SCS‐preserved livers. GM are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells whose presence is linked with the oxidative stress following the IRI.…”

Mitochondrial Targeting Therapy Role in Liver Transplant Preservation Lines: Mechanism and Therapeutic Strategies

“…The gold standard preservation technique for organ transplantation is simple/static cold storage (SCS), which has been used widely and was first introduced by Geoffrey Collins in 1969. This technique enlists the use of standard preservation solutions such as the University of Wisconsin (UW) solution, histidine-tryptophan-ketoglutarate (HTK), and Celsior solutions on ice, at low temperatures (2°C to 4 °C) for liver graft preservation [ 14 ]. Despite the benefits from this standard technique, tissue injury is still an issue especially in the ECD grafts or extended CIT.…”