Evolving Trends in Machine Perfusion for Liver Transplantation Phillipp Dutkowski  Gastroenterology  Volume 156, Issue 6, Pages 1542-1547 (May 2019) DOI: 10.1053/j.gastro.2018.12.037 Copyright © 2019 AGA Institute Terms and Conditions

Figure 1 Machine liver perfusion strategies. A, During cold or warm ischemia, liver grafts suffer from lack of oxygen supply, leading to major metabolic alterations at the mitochondrial level.32 First, electron carriers such as NADH (1) are highly reduced, and second, owing to a block in the electron transport chain,32 the citric acid metabolite succinate increases (2), while ATP and ADP decrease (3) and purine metabolites increase (4) (MODE 1 of mitochondrial operation according to Murphy).33 B, Upon normothermic reperfusion, rapid oxidation of the accumulated succinate (1) together with low adenine nucleotide levels (2) and a reduced coenzyme Q pool trigger reverse instead of forward electron transfer (RET) (3) through the mitochondrial respiratory chain,32 which has been recognized as major generator of reactive oxygen species (ROS) at complex I (4).33 Increased ROS release can also occur at the flavin mononucleotide site of complex I by an increased NADH/NAD ratio. Subsequently, ROS release will initiate an inflammatory cascade34 during NMP (MODE 1 or MODE 2 of mitochondrial operation according to Murphy.33 C, In contrast, during hypothermic/subnormothermic perfusion, mitochondrial respiratory function is significantly slowed down,50 preventing the accumulation of electron overload at complexes I (CI) and II (CII). At the same time, ATP and ADP are resynthesized by the (1) purine salvage pathway,38 leading to an efficient energy charge reload together with succinate metabolism within 1–2 hours.41 Mitochondria are therefore prepared to function normal (forward electron flow (2)) by hypothermic/subnormothermic perfusion with oxidized NADH pool and sufficient ATP/ADP before implantation (MODE 3 of mitochondrial operation according to Murphy.33 CIII, complex III; CIV, complex IV. Gastroenterology 2019 156, 1542-1547DOI: (10.1053/j.gastro.2018.12.037) Copyright © 2019 AGA Institute Terms and Conditions