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Updated: Mar 29, 2026
Normothermic Ex Vivo Liver Machine Perfusion in Mouse
Published on: September 25, 2023
Hypothermic machine perfusion attenuates DCD liver ischemia reperfusion injury via the YAP1/P53-mediated
Jia Liu1, Zhongzhong Liu2, Qifa Ye2
1Department of Transplantation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China.
Abstract:
Donation after circulatory death (DCD) livers are subjected to severe ischemia-reperfusion injury (IRI) during transplantation. Hypothermic machine perfusion (HMP) offers superior mitochondria protection compared with conventional cold storage (CS), yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the mechanistic basis of HMP protection using a rat DCD liver model combined with an in vitro hypoxia/reoxygenation model in human umbilical vein endothelial cells (HUVECs). Rats were subjected to 30 min of warm ischemia followed by CS, HMP and normothermic machine perfusion (NMP). HMP significantly ameliorated liver dysfunction, histopathological damage, oxidative stress and inflammation compared with CS. Mechanistically, HMP upregulated yes-associated protein 1 (YAP1) expression and promoted P53 nuclear translocation, thereby enhancing the expression of microautophagy-related proteins including mitochondria-eating protein (MIEAP), BCL2 interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L), and facilitating the formation of mitochondrial-derived vesicles (MDVs). These effects were abrogated by the YAP1 inhibitor verteporfin in vivo and by YAP1 knockdown or MIEAP silencing in vitro. Collectively, our findings demonstrate that HMP reduced oxidative damage and inflammation of DCD liver through YAP1/P53-mediated micromitophagy.
Insights
Hypothermic machine perfusion (HMP) protects Donation after Circulatory Death (DCD) livers from ischemia-reperfusion injury by activating YAP1/P53-mediated micromitophagy, reducing oxidative damage and inflammation.
Area of Science:
- Transplantation immunology
- Organ preservation
- Cellular mechanisms of injury
Background:
- Donation after circulatory death (DCD) livers suffer significant ischemia-reperfusion injury (IRI) during transplantation.
- Hypothermic machine perfusion (HMP) shows promise in protecting mitochondria better than cold storage (CS), but mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms behind HMP's protective effects in DCD liver transplantation.
- To compare HMP with cold storage (CS) and normothermic machine perfusion (NMP) in a rat DCD liver model.
Main Methods:
- Utilized a rat DCD liver model and an in vitro hypoxia/reoxygenation model with human umbilical vein endothelial cells (HUVECs).
- Compared liver function, histopathology, oxidative stress, and inflammation after CS, HMP, and NMP.
- Investigated the role of YAP1, P53, MIEAP, BNIP3, and BNIP3L in HMP-induced protection.
- Used YAP1 inhibitor (verteporfin), YAP1 knockdown, and MIEAP silencing to confirm mechanisms.
Main Results:
- HMP significantly reduced liver dysfunction, damage, oxidative stress, and inflammation compared to CS.
- HMP upregulated yes-associated protein 1 (YAP1) and promoted P53 nuclear translocation.
- This led to increased expression of microautophagy-related proteins (MIEAP, BNIP3, BNIP3L) and mitochondrial-derived vesicle (MDV) formation.
- Inhibition of YAP1 or MIEAP abolished HMP's protective effects.
Conclusions:
- HMP protects DCD livers from IRI by activating the YAP1/P53 pathway.
- This pathway enhances micromitophagy, reducing oxidative damage and inflammation.
- HMP represents a superior preservation strategy for DCD liver transplantation compared to CS.
