Table 1.
Similarities and differences between apoptosis, necrosis, autophagy and parthanatos
| Apoptosis | Necrosis | Autophagy | Parthanatos | |
|---|---|---|---|---|
| Variations/Subsets in the literature | Caspase-dependent intrinsica | Random or unregulated | Macroautophagy | |
| Caspase-independent intrinsicb | Programmed or regulated, e.g. necroptosis(some think parthanatos could also be considered a case of regulated necrosis) | Microautophagy | ||
| Extrinsic apoptosis by death receptorsc | Chaperone-mediated autophagy | |||
| Extrinsic apoptosis by dependence receptorsd | Mitophagy(but here we consider autophagy as macroautophagy) | |||
| (Biochemical) Signatures | ||||
| Mitochondrial | Caspase activation (except in b) | Loss of ultrastructure | Degradation | Depolarization |
| Mitochondrial depolarization | Swelling | Irreversible Δψm dissipation | ||
| MOMPa,c | ATP and NADH depletion | |||
| Irreversible Δψm dissipationa | AIF release | |||
| CYT c release | CYT c release | |||
| Release of IMS proteinsb | Caspase activation (late stage, non-obligatory) | |||
| Respiratory chain inhibitionb | ||||
| BID cleavagec | ||||
| PP2A activationd | ||||
| DAPK1 activationd | ||||
| Cytoplasmic | Shrinkage | Swelling (including of organelles) | Massive vacuolization | PAR polymer accumulation |
| Vacuolation | Lysosomal degradation | PAR-AIF interactions (binding) | ||
| Organellar disintegration | MAP1LC3 lipidation | Condensation | ||
| AIF translocation to the nucleus | ||||
| Nuclear | PARP cleavage | Chromatin digestion | SQSTM1 degradation | Rapid PARP-1 activation (not cleavage) |
| Chromatin condensation | DNA hydrolysis (smear) | PARP-1-mediated PAR synthesis | ||
| DNA fragmentation (small-scale, DNA ladder) | Chromatin condensation | |||
| PAAN activation (putative) | ||||
| DNA fragmentation (large-scale, ≈50 kb) | ||||
| Structural (plasma membrane) changes | Membrane integrity preserved | Loss of integrity | Double membrane-bound autophagosomes formed | Loss of integrity |
| Formation of apoptotic bodies | Blebbing | Phosphatidylserine externalization | ||
| Membrane blebbing | Cell lysis | |||
| Phosphatidylserine externalization | ||||
| Examples of trigger factors and/or conditions | Death receptor signallingc | Excitotoxicity | Amino acid starvation | Excitotoxicity |
| Dependence receptor signallingd | Ischaemia | Serum starvation | Ischaemia | |
| DNA damage | Stroke | Protein aggregates | DNA damage | |
| Trophic factor withdrawal | Reactive oxygen/nitrogen species | Stroke | ||
| Viral infections | Reactive oxygen/nitrogen species | |||
| Energy (ATP) requirement | + | − | + | − |
| (Obligatory) Caspase-dependence | +a,c,d | − | − | − |
| −b | ||||
| Inflammatory component | − | + | − | − |
| Major mediator(s) | Caspases (except in b) | Calpains, CYPD, RIP-1, RIP-3 (and PARP-1 and AIF, if parthanatos is considered regulated necrosis), etc. | ATG5, ATG6 (Beclin-1), ATG7, ATG12, VPS34, AMBRA-1 | PARP-1 |
| PAR | ||||
| AIF | ||||
| Pharmacological inhibition | Caspase inhibitors, e.g. Z-VAD-fmk (except in b) | RIP-1 inhibitors, e.g. necrostatin-1, calpain inhibitors, etc. | VPS34 inhibitors, e.g. 3-methyladenine and wortmannin | PARP-1 inhibitors, e.g. DPQ |
| Genetic inhibition (knockout/mutation, RNAi targeting) or inhibition by protein overexpression | BCL2 overexpressiona, b | Inhibition of RIP-1 or RIP-3 | Inhibition of AMBRA1, ATG5, ATG7, ATG12 or BECN1 | PARP-1 knockout, AIF down-regulation (e.g. in Harlequin mouse) |
| Inhibition of caspases (3, 8 and 9)c,d | ||||
| Inhibition of PP2Ad | ||||
| CrmA expressionc | ||||
Major similarities and differences in the biochemical, structural and other changes that occur in apoptosis, necrosis, autophagy and parthanatos as some types of cell death, as adapted from (Bredesen et al., 2006; Wang et al., 2009a; Galluzzi et al., 2012). For apoptosis, superscripts have been used where necessary to link each of its different subsets or variations to features that distinguish it. It is worthy to note that, while parthanatos is generally considered to be separate and distinct from necrosis, some investigators consider it to be a specific case of regulated necrosis, just as is necroptosis. Δψm is mitochondrial transmembrane potential.
AIF, apoptosis-inducing factor; AMBRA1, activating molecule in Beclin-1-regulated autophagy protein 1; ATG, autophagy; BCL2, B-cell lymphoma 2; BECN1, Beclin-1; CrmA, cytokine response modifier A; CYPD, cyclophilin D; CYT, cytochrome; DAPK1, death-associated protein kinase 1; DPQ, 3,4-Dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone; IMS, intermembrane space; MAP1LC3, microtubule-associated protein 1 light chain 3; MOMP, mitochondrial outer membrane permeabilization; PAAN, parthanatos AIF-associated nuclease; PAR, poly (ADP-ribose); PP2A, protein phosphatase 2A; RIP, receptor-interacting protein; SQSTM1, sequestosome 1; VPS, vacuolar protein sorting; Z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.