Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

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.