Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria

Abstract

Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.

Biomolecular Pathways of Cryoinjuries in Low-Temperature Storage for Mammalian Specimens

“…Here, we summarized the molecular mechanisms of induction and development of cryogenic damage in low-temperature preservation of mammalian biospecimens, including apoptosis, necroptosis, and IRI. Particularly, mitochondria play a central role in the induction and development of cryoinjuries in all kinds of low-temperature preservation methods and, thus, can be generally regarded as an intervention target to improve preservation outcomes [ 129 , 130 ]. Overall, these molecular mechanisms of cryoinjuries in biopreservation provide general guidance to discover cryoprotective agents, design storage solutions, and develop preservation protocols.…”

Mitochondria and ischemia reperfusion injury

“…Another consequence of oxidative damage is the opening of the mitochondrial permeability transition pore (mPT-Pore) with subsequent release of mitochondrial DNA (mtDNA) and other molecules classified as danger associated molecular pattern (damps), that further pronounce downstream inflammation and later immune response. In addition to mtDNA, severely-injured and apoptotic mitochondria release further damps including ATP, cardiolipin, mitochondrial transcription factor A, succinate, cytochrome-c and N -formyl peptides [4 ▪ ,25]. Such molecules facilitate the activation of another key molecule, the NLRP-3 inflammasome, which in turn triggers the downstream release of cytokines [26–30].…”

“…To successfully limit the various consequences of the IRI-cascade, the field should aim for a wider understanding of specific underlying subcellular mechanisms, which are essential to develop strategies to mitigate this critical cascade. Mitochondria, with their immediate release of reactive oxygen species (ROS) are at the frontline of research interests today [3 ▪▪ ,4 ▪ ]. An increasing body of literature exists, where authors describe the underlying trigger-mechanisms of IRI, which essentially are the same in all solid organs, currently used for transplantation.…”

Hypothermic Machine Perfusion of the Liver. The Reasons for Success

“…While certain protective effects occur naturally due to the impact of organ cooling and lower oxygen requirements, the following detrimental metabolic effects were also identified. During any type of ischemia, a shift towards an anaerobic metabolism occurs, which is based on mitochondrial dysfunction with a lack of Adenosine-trisphosphate (ATP), a calcium overload and the accumulation of certain metabolites in the cell and mitochondria 2 . The lack of oxygen puts the electron flow throughout the respiratory chain on hold with two main metabolic consequences, first the lack of ATP and secondly the accumulation of NADH at a non-functional complex I. Additionally, the impaired function of the Krebs cycle leads to an accumulation of Succinate together with a Complex II dysfunction 3,4 .…”