Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

Abstract

In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.

Figure 1

Role of mitochondrial damage in programmed cell death and preventive function of fusion, fission, and mitophagy. A partially altered mitochondrion (with blue blot) undergoes mitochondrial fission, leading to impaired mitochondria and a healthy small partner (without blue blot). The impaired components of mitochondria are eliminated through mitophagy. The two small healthy mitochondria generated undergo mitochondrial fusion to attenuate mitochondrial stress and restore mitochondrial function. However, when damage accumulates, a severely damaged whole mitochondrion is removed by mitophagy, and when the damage reaches a critical level, mitochondria will initiate programmed cell death.

Figure 2

Mechanisms of mitochondrial regulation of apoptosis and necroptosis. Apoptosis proceeds mainly through the extrinsic and the intrinsic pathway. The TNFR superfamily (e.g., FAS, TNFR1, or DR4/DR5) is activated and interacts with death receptor ligands, FASL, TNF, or TRAIL. For example, TNF binds to and activates TNFR, recruiting the adaptor molecule FADD. Together, these proteins activate caspase 8, which cleaves and stimulates downstream caspase 3 and 7, which target hundreds of cellular components leading to rapid cell apoptosis. The pathway of mitochondrial-dependent apoptosis is instigated by intrinsic stimuli (including oxidative damage, DNA damage, growth factor depletion, or Ca²⁺ overload), which cause activation of BH3-only proteins. BH3-only proteins activate the effector proapoptotic proteins BAX and BAK, resulting in MOMP. Then, MOMP leads to the release of mitochondrial intermembrane space proteins, including cytochrome c. Cytochrome c interacts with APAF1, generating a special set of proteins called the apoptosome. The apoptosome interacts with caspase 9, which stimulates caspases 3 and 7. MOMP contributes to the release of cytochrome and SMAC. SMAC blocks the E3 ubiquitin-protein ligase XIAP (an inhibitor of caspases 3/7), promoting apoptosis. (b) After death receptor activation, the function of caspase 8 determines whether the cell undergoes apoptosis or necroptosis. If caspase 8 activation is inhibited, TNF signaling induces the activation of RIPK1 and RIPK3. RIPK3 phosphorylates and binds to MLKL causing the generation of necrosomes. The necrosome can be shuttled to the mitochondrial membrane and cause mitochondrial membrane permeabilization via a different mechanism of apoptosis. The necrosome also activates the mitochondrial pyruvate dehydrogenase (PDH) complex, enhancing aerobic respiration and ROS generation. In turn, ROS can increase the activation of RIPK3 and promote necrosome assembly.

Figure 3

Mechanisms of mitochondrial involvement in hepatocyte death and fibrosis in chronic liver diseases. ROS can weaken β-oxidation, oxidize fat deposits, and prevent electrons from flowing along with the MRC. Disease factors such as chronic viral infection can contribute to increasing ROS levels and accelerated lipid peroxidation. Lipid peroxidation products increase the hepatic production of TGF-β, which activates hepatic stellate cells, leading to fibrosis. ROS also increase the synthesis of TNF and several other cytokines in the liver, which can cause apoptosis and necroptosis. Necroptosis induces mitochondrial DAMPS, which contribute to the production of inflammatory cytokines that promote liver inflammation.

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.