Parthanatos

While necrosis is caused by acute cell injury resulting in traumatic cell death and apoptosis is a highly controlled process signalled by apoptotic intracellular signals, parthanatos is caused by the accumulation of Poly(ADP ribose) (PAR) and the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria.

PARP-1 mediates parthanatos when it is over-activated in response to extreme genomic stress and synthesizes PAR which causes nuclear translocation of AIF.

Parthanatos was first discovered in a 2006 paper by Yu et al. studying the increased production of mitochondrial reactive oxygen species (ROS) by hyperglycemia.

Researchers noticed that high glucose concentrations led to overproduction of reactive oxygen species and rapid fragmentation of mitochondria.

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.

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.

It belongs to the PARP family, which is a group of catalysts that transfer ADP-ribose units from NAD (nicotinamide dinucleotide) to protein targets, thus creating branched or linear polymers.

PAR causes translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus where it induces DNA fragmentation and ultimately cell death.

While considerable success has been made in understanding the molecular events in parthanatos, efforts are still ongoing to completely identify all of the major players within the pathway, as well how spatial and temporal relationships between mediators affect them.

Extreme damage of DNA causing breaks and changes in chromatin structure have been shown to induce the parthanatos pathway.

[10][13][14] 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.

PAR, which is responsible for the activation of AIF, is regulated in the cell by the enzyme poly(ADP-ribose) glycohydrolase (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.

[29] The same research also showed highly increased PARP activation in dopamine producing cells in the presence of MPTP.

In the neurons of individuals with Parkinson's disease, alpha-synuclein is deposited as fibrils in intracytoplasmic structures referred to as Lewy bodies.

[31] Parthanatos, as a cell death pathway, is being increasingly linked to several syndromes connected with specific tissue damage outside of the nervous system.

However, in high doses, STZ has been shown to produce diabetic symptoms by damaging pancreatic β cells, which are insulin-producing.