Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia/reperfusion injury via phospholipid metabolism‐mediated mitochondrial quality control

Abstract

Mitochondrial dysfunction is the leading cause of reactive oxygen species (ROS) burst and apoptosis in hepatic ischemia/reperfusion (I/R) injury. Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatotargeted agent that exerts hepatoprotective roles by regulating lipid metabolism. Our previous studies have shown that UDCA-LPE improves hepatic I/R injury by inhibiting apoptosis and inflammation. However, the role of UDCA-LPE in lipid metabolism and mitochondrial function in hepatic I/R remains unknown. In the present study, we investigated the role of UDCA-LPE in hepatic I/R by focusing on the interface of phospholipid metabolism and mitochondrial homeostasis. Livers from 28-week-old mice, primary hepatocytes and HepG2 cells were subjected to in vivo and in vitro I/R, respectively.Analyses of oxidative stress, imaging, ATP generation, genetics, and lipidomics showed that I/R was associated with mitochondrial dysfunction and a reduction in phospholipids. UDCA-LPE alleviated mitochondria-dependent oxidative stress and apoptosis and prevented the decrease of phospholipid levels. Our study found that cytosolic phospholipase A 2 (cPLA 2 ), a phospholipase that is activated during I/R, hydrolyzed mitochondrial membrane phospholipids and led to mitochondria-mediated oxidative stress and apoptosis. UDCA-LPE inhibited the interaction between cPLA 2 and mitochondria and reduced phospholipid hydrolysis-mediated injury. UDCA-LPE might regulate the crosstalk between the phospholipid metabolism and the mitochondria, restore mitochondrial function and ameliorate I/R injury. K E Y W O R D ScPLA 2 , defect mitochondria, mitochondrial membrane, oxidative stress, phospholipid metabolism disorders, reperfusion injury | 6199 GU et al.

Exosomes from adipose‐derived mesenchymal stem cells alleviate liver ischaemia reperfusion injury subsequent to hepatectomy in rats by regulating mitochondrial dynamics and biogenesis

“…In this study, the morphology of hepatocytes revealed that the damage of mitochondria was significantly reduced after ADSCs‐exo treatment. As regard the ATP production our results were consistent with those of previous studies, 35,36 since the ATP content in the liver of the I30R+PH group was significantly lower than that in the Sham group, which might be due to a direct consequence of impaired mitochondrial dynamics. ADSCs‐exo treatment reversed the decrease of ATP content caused by HIRI subsequent to hepatectomy.…”

Role of Mitochondrial Pathways in Cell Apoptosis during He-Patic Ischemia/Reperfusion Injury

“…These fragmented organelles fuse to an interconnected network which renews the damaged mitochondrial DNA (mtDNA) [25]. Excessive fission causes mitochondrial breakage and activates its apoptosis pathway, thus aggravating tissue damage and cell apoptosis [26]. Additionally, excessive fission of mitochondria is a pre-symptom of cytochrome-C (cyt c) release [27], and the release of cyt c further promotes the mitosis of mitochondria.…”

“…Mitochondrial fusion has long been regarded as a protective way to reduce mitochondrial fission [9]. During hepatic IRI, the fusion of damaged mitochondria could cause a beneficial effect to maintain the survival function of mitochondria [26] by preventing mitochondrial decomposition caused by the release of cyt c, xanthine oxidase (XO), and ROS in mitochondrial [31]. Fusion is associated with the redistribution of metabolites, proteins, and mtDNA in mitochondria.…”

“…Firstly, hypoxia has been reported to be an effective disruptor of oxidative phosphorylation, hindering the production of ATP and leading to Ca 2+ overload [20]. It was suggested that the extent mitochondrial Na + /Ca 2+ commutator overburdened and inactive state exacerbated with Ca 2+ overload, causing the concentration of Ca 2+ to increase enough to trigger the activation of MPTP opening [26,74]. Secondly, the increase in intracellular Ca 2+ content induces the formation of protein kinase C (PKC).…”

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation

“…Cytosolic phospholipase A2 (PLA2), a phospholipase, hydrolyzed mitochondrial membrane phospholipids and resulted in mitochondria-mediated oxidative stress and apoptosis. Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) could regulate the crosstalk between the phospholipid metabolism and mitochondria, restore mitochondrial function and alleviate IRI [ 36 ]. During liver IRI, mitochondrial permeability transition pore opening leads to the dysfunction of mitochondria.…”