In:
eLife, eLife Sciences Publications, Ltd, Vol. 7 ( 2018-04-20)
Abstract:
Despite their importance as signaling hubs, the function of mitochondria-ER contact sites in mitochondrial quality control pathways remains unexplored. Here we describe a mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin. Mitochondria-ER appositions are destroyed during mitophagy, and reducing mitochondria-ER contacts increases the rate of mitochondrial degradation. Mechanistically, parkin/PINK1 catalyze a rapid burst of Mfn2 phosphoubiquitination to trigger p97-dependent disassembly of Mfn2 complexes from the outer mitochondrial membrane, dissociating mitochondria from the ER. We additionally demonstrate that a major portion of the facilitatory effect of p97 on mitophagy is epistatic to Mfn2 and promotes the availability of other parkin substrates such as VDAC1. Finally, we reconstitute the action of these factors on Mfn2 and VDAC1 ubiquitination in a cell-free assay. We show that mitochondria-ER tethering suppresses mitophagy and describe a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondria-ER contact sites.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.32866.001
DOI:
10.7554/eLife.32866.002
DOI:
10.7554/eLife.32866.004
DOI:
10.7554/eLife.32866.003
DOI:
10.7554/eLife.32866.005
DOI:
10.7554/eLife.32866.006
DOI:
10.7554/eLife.32866.007
DOI:
10.7554/eLife.32866.013
DOI:
10.7554/eLife.32866.008
DOI:
10.7554/eLife.32866.009
DOI:
10.7554/eLife.32866.010
DOI:
10.7554/eLife.32866.011
DOI:
10.7554/eLife.32866.012
DOI:
10.7554/eLife.32866.014
DOI:
10.7554/eLife.32866.016
DOI:
10.7554/eLife.32866.015
DOI:
10.7554/eLife.32866.017
DOI:
10.7554/eLife.32866.018
DOI:
10.7554/eLife.32866.019
DOI:
10.7554/eLife.32866.021
DOI:
10.7554/eLife.32866.020
DOI:
10.7554/eLife.32866.022
DOI:
10.7554/eLife.32866.023
DOI:
10.7554/eLife.32866.024
DOI:
10.7554/eLife.32866.026
DOI:
10.7554/eLife.32866.025
DOI:
10.7554/eLife.32866.027
DOI:
10.7554/eLife.32866.028
DOI:
10.7554/eLife.32866.029
DOI:
10.7554/eLife.32866.031
DOI:
10.7554/eLife.32866.032
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2018
detail.hit.zdb_id:
2687154-3
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