Parthanatos
Parthanatos (derived from the Greek Θάνατος, "
History
Name
The term parthanatos was not coined until a review in 2009.[1] The word parthanatos is derived from Thanatos, the personification of death in Greek mythology.
Discovery
Parthanatos was first discovered in a 2006 paper by Yu et al. studying the increased production of mitochondrial reactive oxygen species (ROS) by hyperglycemia.[3] This phenomenon is linked with negative effects arising from clinical complications of diabetes and obesity.
Researchers noticed that high glucose concentrations led to overproduction of reactive oxygen species and rapid fragmentation of mitochondria. Inhibition of mitochondrial pyruvate uptake blocked the increase of ROS, but did not prevent mitochondrial fragmentation. After incubating cells with the non-metabolizable stereoisomer L-glucose, neither reactive oxygen species increase nor mitochondrial fragmentation were observed. Ultimately, the researchers found that mitochondrial fragmentation mediated by the fission process is a necessary component for high glucose-induced respiration increase and ROS overproduction.[citation needed]
Extended exposure to high glucose conditions are similar to untreated diabetic conditions, and so the effects mirror each other. In this condition, the exposure creates a periodic and prolonged increase in ROS production along with mitochondrial morphology change. If mitochondrial fission was inhibited, the periodic fluctuation of ROS production in a high glucose environment was prevented. This research shows that when cell damage to the ROS is too great, PARP-1 will initiate cell death.[citation needed]
Morphology
Structure of PARP-1
Poly(ADP-ribose) polymerase-1 (
Role of PARP-1
Normally, PARP-1 is involved in a variety of functions that are important for cell
Role of PAR
PARP-1 accomplishes many of its roles through regulating poly(ADP-ribose) (PAR). PAR is a
Pathway
The parthanatos pathway is activated by
Pathway activation
Extreme damage of DNA causing breaks and changes in
The magnitude, length of exposure, type of cell used, and purity of the culture, are all factors that can influence the activation of the pathway.
Cell death initiation
Once the PARP-1 protein recognizes the DNA damage, it
PARG
PAR, which is responsible for the activation of AIF, is regulated in the cell by the enzyme poly(ADP-ribose) glycohydrolase (PARG). After PAR is synthesized by PARP-1, it is degraded through a process catalyzed by PARG.[20] PARG has been found to protect against PAR-mediated cell death[9] while its deletion has increased toxicity through the accumulation of PAR.[9]
Other proposed mechanisms
Before the discovery of the PAR and AIF pathway, it was thought that the overactivation of PARP-1 lead to over consumption of
Differences between cell death pathways
Parthanatos is defined as a unique cell death pathway from
While parthanatos does share similarities with necrosis, is also has several differences. Necrosis is not a regulated pathway and does not undergo any controlled nuclear fragmentation. While parthanatos does involve loss of cell membrane integrity like necrosis, it is not accompanied by cell swelling.[26]
Comparison of cell death types
Parthanatos | Apoptosis | Necrosis | |
---|---|---|---|
Chromatin Condensation | Yes | Yes | No |
Nuclear fragmentation | Yes | Yes | No |
Apoptotic bodies | No | Yes | No |
Mitochondrial Swelling | No | Sometimes | Yes |
Membrane Blebbing | No | Yes | Yes, late |
Caspase Dependent | No | Yes | Sometimes |
Regulated Pathway | Yes | Yes | No |
Pathology and treatment
Neurotoxicity
The PAR enzyme was originally connected to neural degradation pathways in 1993. Elevated levels of
PARP activity has also been linked to the neurodegenerative properties of toxin induced
Alpha-synuclein is a protein that binds to DNA and modulates DNA repair.[30] A key feature of Parkinson's disease is the pathologic accumulation and aggregation of alpha-synuclein. In the neurons of individuals with Parkinson's disease, alpha-synuclein is deposited as fibrils in intracytoplasmic structures referred to as Lewy bodies. Formation of pathologic alpha-synuclein is associated with activation of PARP1, increased poly(ADP) ribose generation and further acceleration of pathologic alpha-synuclein formation.[31] This process can lead to cell death by parthanatos.[31]
Multisystem involvement
Parthanatos, as a cell death pathway, is being increasingly linked to several
PARP activation has also been preliminarily connected with
Therapy
The multi-step nature of the parthanatos pathway allows for chemical manipulation of its activation and inhibition for use in therapy. This rapidly developing field seems to be currently focused on the use of PARP blockers as treatments for chronically degenerative illnesses. This culminated in 3rd generation inhibitors such as midazoquinolinone and isoquinolindione currently going to clinical trials.[8]
Another path for treatments is to recruit the parthanatos pathway to induce apoptosis into cancer cells, however no treatments have passed the theoretical stage.[8]
See also
- Apoptosis inducing factor
- Programmed cell death
- PARP1
References
- ^ PMID 19273119.
- PMID 31820165
- PMID 16477035.
- PMID 23917125.
- PMID 25813046.
- PMID 6311052.
- ^ PMID 1736995.
- ^ PMID 24684389.
- ^ PMID 17116882.
- ^ S2CID 22991897.
- S2CID 11987578.
- PMID 16239930.
- PMID 11526447.
- S2CID 19992518.
- S2CID 31015078.
- PMID 10455009.
- ^ PMID 11447231.
- PMID 21467298.
- S2CID 34432364.
- PMID 6325408.
- PMID 6317637.
- PMID 2943264.
- ^ Ha HC, Snyder SH. 1999. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A 96: 13978–13982
- PMID 21366272.
- PMID 19332058.
- PMID 15574746.
- ^ PMID 7684776.
- PMID 6823561.
- PMID 10318960.
- PMID 31358782.
- ^ PMID 30385548.
- PMID 22330251.
- PMID 6251809.
- S2CID 7794573.
- PMID 9922314.
- PMID 3142482.