Parkin and PINK1 mitigate STING-induced inflammation, 2018, Youle et al

Andy · Aug 27, 2018

Abstract

Although serum from patients with Parkinson’s disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown1. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson’s disease2,3. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy4. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson’s-disease-relevant phenotypes5,6,7. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8,9,10,11,12, suggesting that mitophagy may mitigate inflammation.

Here we report a strong inflammatory phenotype in both Prkn−/− and Pink1−/− mice following exhaustive exercise and in Prkn−/−;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA)13,14. Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA15,16. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn−/−;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity.
Click to expand...

Paywalled at https://www.nature.com/articles/s41586-018-0448-9

Article from Nature about this study

Elusive mitochondrial connection to inflammation uncovered

Neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases constitute a major human-health burden. Although the symptoms, or the cells affected, can differ in such disorders, some neurodegenerative diseases have certain characteristics in common. These include a state of inflammation1 and impaired elimination of defective mitochondrial organelles2. However, it remains to be determined whether such common alterations are interconnected, and whether they are a cause or a consequence of disease. Writing in Nature, Sliter et al.3 report their investigation of mice that have alterations in genes linked to Parkinson’s disease. The authors identify a direct connection between the cellular process that eliminates damaged mitochondria — called mitophagy — and inflammation.
Click to expand...

https://www.nature.com/articles/d41586-018-05988-z

Log in or Sign up

Parkin and PINK1 mitigate STING-induced inflammation, 2018, Youle et al

Andy Committee Member

Share This Page

Log in or Sign up

Parkin and PINK1 mitigate STING-induced inflammation, 2018, Youle et al

Andy Committee Member

Share This Page

Useful Searches