Increased oxidative stress caused by impaired mitophagy aggravated liver ischemia and reperfusion injury in diabetic mice

Abstract

Aims/Introduction Emerging evidence has suggested the detrimental role of oxidative stress in aggravating ischemia and reperfusion (IR) injury in diabetic livers. Interplay between oxidative stress and mitophagy has been shown. However, the role and mechanism of mitophagy in regulating oxidative stress and IR injury in diabetic livers remain unclear. Materials and Methods Wild‐type and db / db (DB) mice were subjected to a partial warm liver IR model. Liver injury, oxidative stress, mitophagy and related molecular pathways were analyzed. Results Here, we found that increased liver IR injury was observed in DB mice, as evidenced by higher levels of serum alanine aminotransferase and serum aspartate, worsened liver architecture damage and more hepatocellular death. DB mice also showed increased mitochondrial oxidative stress. Mitochondrial reactive oxygen species scavenge alleviated liver IR injury in DB mice. Mechanistic analysis showed that 5′ adenosine monophosphate‐activated protein kinase‐mediated mitophagy was suppressed in DB mice post‐IR. Pharmacological activation of 5′ adenosine monophosphate‐activated protein kinase by its agonist effectively restored mitophagy activation, leading to decreased mitochondrial oxidative stress and attenuated liver IR injury in DB mice. Conclusions Our findings showed that diabetes increased oxidative stress to exacerbate liver IR injury by impairing 5′ adenosine monophosphate‐activated protein kinase‐mediated mitophagy. Strategies targeting oxidative stress and mitophagy might provide a promising approach to ameliorate liver IR injury in diabetes patients.

Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury

“…In a recent study, stimulation of mitophagy using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, during I/R in diabetic mice improved an already aggravated I/R injury. Oxidative stress was attenuated and PINK1/Parkin-related mitophagy was stimulated [ 68 ]. Besides being deeply involved in the regulation of energy metabolism, AMPK also regulates a variety of aspects crucial for mitochondrial homeostasis.…”

Mitochondrial quality control in hepatic ischemia-reperfusion injury

“…AMPK also plays an important role in the activation of mitophagy [ 79 ]. In liver I/R injury in diabetic mice, activation of AMPK effectively restored mitophagy activation, leading to decreased mitochondrial oxidative stress and attenuated liver I/R injury [ 103 ]. This implies that mitochondrial autophagy is governed by other proteins within the mitochondria, creating a complex regulatory network.…”

Modified Buyang Huanwu Decoction alleviates diabetic liver injury via inhibiting oxidative stress in db/db mice

“…This categorization implies that the TCM syndromes of DM patients with liver complications are primarily liver-kidney co-diseases, with Yin deficiency playing a significant role in the pathogenesis. Modern research supports this view, demonstrating that DM complicated by liver and kidney injury influences each other, with OS playing a crucial role in the pathogenesis [13,14]. The Buyang Huanwu Decoction (BYHWD) is known for its anti-inflammatory [15], antioxidant [16,17], and vascular and nerve regeneration properties [18].…”