Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts Journal Article
| Authors: | Fung, T. S.; Ghosh, A.; Zavala, M. R.; Nichtova, Z.; Shukal, D.; Tigano, M.; Csordas, G.; Higgs, H. N.; Chakrabarti, R. |
| Article Title: | Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts |
| Abstract: | Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage. |
| Keywords: | actin; er; activation; endoplasmic-reticulum; recruitment; complex; mechanisms; cleavage; lc3; membranes; parkin; mitofusin 2; mitophagy; arp2/3 complex; pink1 |
| Journal Title: | EMBO Reports |
| ISSN: | 1469-221X |
| Publisher: | Wiley Blackwell |
| Publication status: | Online ahead of print |
| Date Published: | 2025-01-01 |
| Online Publication Date: | 2025-01-01 |
| Language: | English |
| ACCESSION: | WOS:001563315000001 |
| DOI: | 10.1038/s44319-025-00561-y |
| PROVIDER: | wos |
| Notes: | Article; Early Access -- Source: Wos |
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