Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury

Figure 4

Scheme of I/R-induced impairment of autophagy. After reperfusion, hepatocytes become overloaded with ROS and calcium, which in turn stimulates calpains. These enzymes subsequently hydrolyze ATG7 and BECN1, causing defective autophagy. Since impaired autophagy fails to eliminate abnormal mitochondria, the mitochondria laden with ROS and calcium undergo the MPT and ultimately induce cell death. Suppression of calcium increase, inhibition of calpains with acetyl-leu-leu-methioninal, enhancement of autophagy, or blockade of the MPT with cyclosporin A or nitric oxide prevents reperfusion-induced cell death. Damaged hepatocytes subsequently release damage-associated molecular patterns and ROS. Kupffer cells and sinusoidal endothelial cells are then activated, leading to chemokine and cytokine release, neutrophil and platelet activation, and platelet adhesion to the sinusoidal lumen. Congestion and constriction of the sinusoid further aggravate reperfusion injury. AdATG7, adenovirus expressing ATG7; AdBECN1, adenovirus expressing Beclin-1; ALLM, acetyl-leu-leu-methioninal; CsA, cyclosporin A; DAMP, damage-associated molecular patterns; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; Mac-1, macrophage-1 antigen; NO, nitric oxide; ROS, reactive oxygen species.