Studies reveal the mechanisms behind tumor metastasis and how to stymie it. But primary tumors still get the lion’s share of researchers’ attention.
Image courtesy of Science Source/Phanie.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Edited by Don W. Cleveland, University of California, San Diego, La Jolla, CA, and approved August 23, 2016 (received for review July 30, 2016)
Significance
In mitophagy, damaged mitochondria stabilize PTEN-induced putative kinase 1 (PINK1) and recruit Parkin, an E3-ligase that ubiquitinates proteins on the outer membrane and targets mitochondria for degradation. The crucial roles of PINK1 phosphorylation of Parkin and ubiquitin in mitophagy are well-established. Other substrates of PINK1, however, have also been reported but the significance of those phosphorylations is less clear. We now show that Miro phosphorylations can regulate Parkin recruitment to Miro and trigger Miro degradation. The consequence of this branch of the PINK1/Parkin pathway is the disruption of mitochondrial motility, an event that may spatially restrict the deleterious effects of mitochondrial damage prior to the mitophagic removal of the organelle.
Abstract
The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.
Footnotes
- ↵1To whom correspondence should be addressed. Email: Thomas.Schwarz{at}childrens.harvard.edu.
Author contributions: E.S. and T.L.S. designed research; E.S. and T.K. performed research; J.S. and M.J.L. contributed new reagents/analytic tools; E.S. and T.L.S. analyzed data; and E.S. and T.L.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612283113/-/DCSupplemental.
Miro phosphorylation sites regulate Parkin
More Articles of This Classification
Related Content
Cited by...
- No citing articles found.
Similar Articles
You May Also be Interested in
Both social and engineering factors must be further explored and scrutinized across the globe—as should notions of justice related to flooding impacts and responses.
Image courtesy of Shutterstock.com/Ekaterina Pokrovsky.
Blair Hedges discusses the state of Haiti's remaining forests and the consequences to biodiversity.
A study uncovers genetic evidence of early colonization of Jamaica by primates and suggests that adaptation can shape species morphology in novel environments, even when species come from morphologically conservative families.
Image courtesy of Lorraine Meeker (American Museum of Natural History, New York).
Researchers report that some moth species use sound absorbing-scales to avoid detection by bats and suggest that the findings could aid the design of biologically inspired sound absorbers for an array of applications, including noise mitigation and building acoustics.
Image courtesy of Thomas R. Neil.
