PINK1 and parkin are key regulators of mitochondrial quality control. Credit: http://www.sciencedirect.com/…/pii/S0166223614000435
>> potential new pathway to treat ALS, other diseases. When mitochondia are damaged, they leak destructive molecules that can cause substantial harm and eventually kill brain cells. PINK1, a protein implicated in Parkinson’s disease is critical for helping cells get rid of dysfunctional mitochondria, by triggering an intricate process called mitophagy that breaks down and removes damaged mitochondria from the cell.
“PINK1 is a flag of damaged mitochondria,” said Richard Youle, Ph.D., the head of the Biochemistry Section of NINDS. “It identifies which mitochondria need to be eliminated to keep cells healthy.” Mutations in PINK1 and its partner molecule Parkin cause hereditary forms of Parkinson’s disease. Moreover, the inability to remove defective mitochondria from nerve cells has been linked to numerous neurodegenerative diseases, including the more common forms of Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Dr. Youle’s team discovered PINK1 can initiate mitophagy without Parkin. “This changes the model we had previously, and relegates Parkin to an amplifier that increases the mitophagy signal triggered by PINK1′.
MOA: PINK1 recruits 2 proteins Optineurin and NDP52 to the surface of mitochondria. These proteins, in turn, recruit a variety of other protein molecules that mark the mitochondria for degradation. Optineurin and NDP52 are members of a group of proteins called autophagy receptors. When the researchers created cells that contained no autophagy receptors, they found that the cells could not dispose of malfunctioning mitochondria. However, when the group restored the function of either Optineurin or NDP52, the cells regained this ability. Reinstating other autophagy receptors had little or no effect.
PINK1 recruits OPTN and NDP52 independently of parkin to promote mitophagy. Credit: http://www.nature.com/…/ncurrent/full/nature14893.html
Eg. “Optineurin is mutated in ALS and also in certain forms of glaucoma, whereas NDP52 is known to be mutated in Crohn’s disease. This suggests that problems with mitophagy may be involved in those diseases.”
When PINK1 accumulates on the surface of defective mitochondria, it alters ubiquitin >> recruits autophagy receptors + Parkin >> promotes mitophagy by bringing more ubiquitin to the mitochondria to form long chains that flag damaged mitochondria for removal. Since PINK1 is needed to start building these ubiquitin chains, Dr. Youle’s work suggests a new avenue for creating drugs that treat disease by boosting the disposal of damaged mitochondria. “It may not be so important to activate Parkin; it may be more important to activate PINK1.” http://www.ninds.nih.gov/news_and_events/news_articles/pressrelease_pink1_protein_08122015.htm
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