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

Abstract

The normal function of mitochondria in the hepatic parenchyma can be disrupted by ischemia/reperfusion (I/R) damage during liver transplantation. The pathology of these insults involves various cellular and molecular steps of events that have been extensively researched over decades but are yet to provide complete answers. This review discusses the brief mechanism of the pathophysiology following ischemia/reperfusion injury (IRI) and various targeting strategies that could result in improved graft function. The traditional treatment for end-stage liver disease i.e., liver transplantation, has been complicated by I/R damage. The poor graft function or primary non-function found after liver transplantation may be due to mitochondrial dysfunction following IRI. As a result, determining the sequence of incidents that cause human hepatic mitochondrial dysfunction is crucial; it might contribute to further improvements in the outcome of liver transplantation. Early discovery of novel prognostic factors involved in IRI could serve as a primary endpoint for predicting the outcome of liver grafts as well as promoting the early implementation of novel IRI-prevention strategies. In this review, recent developments in the study of mitochondrial dysfunction and I/R damage are discussed, specifically those concerning liver transplantation. Furthermore, we also explore different pharmacological therapeutic methods that may be used and their connections to mitochondrion-related processes and goals. Although significant progress has been made in our understanding of IRI and mitochondrial dysfunction, further research is needed to elucidate the cellular and molecular pathways underlying these processes to help identify biomarkers that can aid donor organ evaluation.

Keywords: graft failure; graft survival; ischemia/reperfusion injury; liver transplantation; mechanism; mitochondrial targeting therapy; pathophysiology; preservation; therapeutics.

Figure 1. LT – Liver transplantation, HS – Hemorrhagic shock. Hepatic IRI can be classified into cold I/R (LT-induced) and warm I/R (e.g. HS-induced); the up-regulating and down-regulating indices are given in the above figure.

Figure 2. SCS - Static cold storage. Schematic representation of different phases of the hepatic ischemic reperfusion injury.

Figure 3. Ischemic preconditioning (IPC) and ischemic post-conditioning (IPostC) mechanisms of action. The mutual mechanisms involved in the operation of IPC and IPostC are depicted in this simplified diagram. In most cases, IPC and IPostC are equally efficient. In several studies, IPC was found to be more effective than IPostC at reducing IRI-induced apoptosis.