Pathways of Apoptotic, Necroptotic, and Necrotic Cell Death
(A) APOPTOSIS. There are 2 basic pathways to mediate apoptosis—the intrinsic pathway or the extrinsic pathway. (Left) The intrinsic pathway, where intracellular triggers like cellular stress lead to mitochondrial permeability transition pore formation, collapsing voltage, leak of cytochrome C, and formation of the apoptosome (a combination of APAF1, Caspase 9, and cytochrome C). This can activate the executioner caspases (3 and 7), resulting in deoxyribonucleic acid (DNA) fragmentation and the classic apoptotic morphology. (Middle) The extrinsic pathway for apoptosis. Engagement of the death receptors (with TNF alpha, FAS, or other ligands) results in TRAD-RIPK1 activation if RIPK1 is disubiquitylated (uRIPK1), and mediates apoptosis via caspase 8 and then by activating the executioner caspases 3 and 7. This again results in DNA fragmentation and apoptosis. In every process of apoptosis, depending on the energetic state, the cell may complete apoptosis if ATP levels are adequate for preserving pumps, enter a zombie state if ATP is marginal, and end in necrosis if ATP levels are depleted so much that that they cannot sustain the membrane pumps. (Right) Possible imaging targets for apoptosis can be exposed to the cell surface or intracellular. The former include exteriorized cell surface phospholipids like phosphatidylethanolamine (PE) and phosphatidylserine (PS), exteriorized histones, and the La antigen that translocates from the nucleus to the cytoplasm (which can be accessed for imaging in later stages of apoptosis). Nonexteriorized targets include probes for mitochondrial voltage and its integrity, and caspase activation. Some gadolinium-based CMR probes can access DNA fragments in later stages of apoptosis. (B) Necroptosis and necrosis. (Left) The necroptosis pathway uses the same pathways as apoptosis but with some differences—should TRAD-RIPK1 activation occur when RIPK1 is disubiquitylated (uRIPK1) and there is caspase 8 inhibition, the cell gets diverted from an apoptotic fate and enters the necroptosis pathway instead. This is mediated via the RIPK3–MLKL complex and results in a necrotic morphology (membrane permeabilization and swelling of mitochondria with ATP depletion). Imaging targets for necroptosis include Nec-I–based probes and finding morphological changes in the membrane and mitochondria that resemble a mixture of apoptosis and necrosis. However, NEC-1 imaging is in a very early stage of development. (Right) Should the damage be severe or should apoptosis or necroptosis present with severe energy depletion, the process morphs into necrosis, a largely irreversible form of cell death. Because necrosis is associated with significantly compromised membranes, imaging targets for necrosis include many of the intracellular components—myosin, dithiols like HSP90, Filamin A, and so on. They can be imaged with a number of nuclear and CMR techniques.