Abstract
Ischemia-reperfusion injury (IRI) has indeed been shown as a main complication of hepatectomy, liver transplantation, trauma, and hypovolemic shock. A large number of studies have confirmed that microvascular and parenchymal damage is mainly caused by reactive oxygen species (ROS), which is considered to be a major risk factor for IRI. Under normal conditions, ROS as a kind of by-product of cellular metabolism can be controlled at normal levels. However, when IRI occurs, mitochondrial oxidative phosphorylation is inhibited. In addition, oxidative respiratory chain damage leads to massive consumption of adenosine triphosphate (ATP) and large amounts of ROS. Additionally, mitochondrial dysfunction is involved in various organs and tissues in IRI. On the one hand, excessive free radicals induce mitochondrial damage, for instance, mitochondrial structure, number, function, and energy metabolism. On the other hand, the disorder of mitochondrial fusion and fission results in further reduction of the number of mitochondria so that it is not enough to clear excessive ROS, and mitochondrial structure changes to form mitochondrial membrane permeable transport pores (mPTPs), which leads to cell necrosis and apoptosis, organ failure, and metabolic dysfunction, increasing morbidity and mortality. According to the formation mechanism of IRI, various substances have been discovered or synthesized for specific targets and cell signaling pathways to inhibit or slow the damage of liver IRI to the body. Here, based on the development of this field, this review describes the role of mitochondria in liver IRI, from aspects of mitochondrial oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures. Therefore, it may provide references for future clinical treatment and research.
Highlights
Liver ischemia-reperfusion injury (IRI) occurs when blood supply is interrupted or sharply reduced, which is the main complication of liver operation, such as hepatectomy, liver transplantation, and trauma [1, 2]
Further experiments have confirmed that Ginsenoside can slow down mitochondrial injury and IRI by inhibiting the cyclophilin D (CypD) pathway [62], and in mouse and human liver tissues, C31, a small molecule inhibitor of CypD, has a high affinity for CypD, which can reduce calcium ion-induced mitochondrial swelling and destruction by blocking the opening of membrane permeable transport pores (mPTPs) to play a role in protecting the liver from IRI [19]
Some other research results show that phosphodiesterase inhibitor cilostazol can promote the expression of NF-E2-related factor-2 (Nrf2) and heme oxygenase 1 (HO-1) to slow down IRI [68, 90, 91] and Brahma-related gene 1 (Brg1) as the core ATPase, whose overexpression increases Nrf2-mediated HO-1 gene transcription to increase antioxidant capacity against liver injury [92]
Summary
Liver ischemia-reperfusion injury (IRI) occurs when blood supply is interrupted or sharply reduced, which is the main complication of liver operation, such as hepatectomy, liver transplantation, and trauma [1, 2]. Liver IRI is divided into two types: Warm IRI occurs in low blood flow states, such as portal vein embolism, cirrhosis, liver resection, and liver transplantation. In this process, the structure and function of mitochondria are damaged, leading to inhibition of oxidative phosphorylation and reduction of adenosine triphosphate (ATP) production and further induce mitochondrial fission, mitochondrial autophagy, and apoptosis [9]. A wide variety of studies have shown that the mechanism of IRI is complex and not very clear, which involves multiple pathways: oxidative stress, inflammatory response, mitochondrial dysfunction, apoptosis, etc Of note, these processes begin during the ischemic phase and strengthen during the reperfusion phase [14,15,16]. This review mainly introduces the mechanisms of mitochondria in IRI from the aspects of oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures to provide references for future clinical treatment and research
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