Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

Figure 4

Mitochondrial dysfunction and liver cirrhosis. In liver cirrhosis, stimuli such as ischaemia, hypoxia, and endotoxaemia contribute to mitochondrial dysfunction. First, exposure of liver cells to a high level of endotoxin from the gastrointestinal tract inhibits enzyme dehydrogenase activity and blocks energy generation, and ROS production increases due to this interference of respiratory chain electron transfer. Second, unbalanced ROS levels lead to altered mitochondrial membrane permeability, induction of inflammatory signaling, and promoted activation of programmed cell death pathways. Additionally, ischaemia and hypoxia in the cirrhotic liver can cause cell membrane destruction, and Ca²⁺-ATPase activity at the cell membrane is inhibited. Ca²⁺ intake is often accompanied by depolarization of the mitochondrial membrane and H⁺ excretion. When the Ca²⁺ concentration in the mitochondria is excessive, inner membrane pores are opened. As a result, mitochondrial membrane permeability is increased. Mitochondria become dysfunctional, which induces programmed cell death, death-related inflammation, the immune response, fibrosis, and regeneration and further aggravates cirrhosis, thereby forming a vicious cycle.