AMBRA1 is Able to Induce Mitophagy Via LC3 Binding, Regardless of PARKIN and P62/SQSTM1

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2014 Sep 13

PMID 25215947

Citations 173

Authors

F Strappazzon

F Nazio

M Corrado

V Cianfanelli

A Romagnoli

G M Fimia

S Campello

R Nardacci

M Piacentini

M Campanella

F Cecconi

Affiliations

Soon will be listed here.

Abstract

Damaged mitochondria are eliminated by mitophagy, a selective form of autophagy whose dysfunction associates with neurodegenerative diseases. PINK1, PARKIN and p62/SQTMS1 have been shown to regulate mitophagy, leaving hitherto ill-defined the contribution by key players in 'general' autophagy. In basal conditions, a pool of AMBRA1 - an upstream autophagy regulator and a PARKIN interactor - is present at the mitochondria, where its pro-autophagic activity is inhibited by Bcl-2. Here we show that, upon mitophagy induction, AMBRA1 binds the autophagosome adapter LC3 through a LIR (LC3 interacting region) motif, this interaction being crucial for regulating both canonical PARKIN-dependent and -independent mitochondrial clearance. Moreover, forcing AMBRA1 localization to the outer mitochondrial membrane unleashes a massive PARKIN- and p62-independent but LC3-dependent mitophagy. These results highlight a novel role for AMBRA1 as a powerful mitophagy regulator, through both canonical or noncanonical pathways.

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