AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1
Open accessAbstract
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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AMBRA1 and ATG12 positively regulate mitophagy.
“Although the role of ATG4A in mitophagy is unclear, AMBRA1 and ATG12 positively regulate mitophagy [56–58].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [57]
The Abstract (page unavailable) identifies AMBRA1 as a mitophagy regulator and reports that directing it to the outer mitochondrial membrane triggers mitophagy. Our copy does not establish that ATG12 positively regulates mitophagy; a search for ATG12 found no passage supporting that part of the claim. (LLM, conf=0.87)
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References 41 · Cited by 399
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- Authors
- Strappazzon, F., Nazio, F., Corrado, M., Cianfanelli, V, Romagnoli, A., Fimia, G. M., Campello, S., Nardacci, R., Piacentini, M., Campanella, M., & Cecconi, F.
- Affiliations
- University of Rome Tor Vergata (IT)
- Fondazione Santa Lucia (IT)
- Veneto Institute of Molecular Medicine (IT)
- Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT)
- University of Salento (IT)
- University of London (GB)
- Corresponding author
- Cecconi, F
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2014-09-12
- Volume
- 22
- Issue
- 3
- Pages
- 419-432
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4326570
- OpenAlex
- W1992947862
- Cited by
- 399
- References
- 41
- Citations by year
- 2026: 21 · 2025: 23 · 2024: 42 · 2023: 34 · 2022: 40 · 2021: 53 · 2020: 41 · 2019: 31 · 2018: 23 · 2017: 33 · 2016: 26 · 2015: 27 · 2014: 4
- FWCI
- 22.73
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-02-09)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Death and Differentiation (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RVC Research Online (Royal Veterinary College) (submittedVersion, cc-by)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-nd)
- Iris (Roma Tre University) (submittedVersion)
- AIRUS (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- Fondazione Telethon (GGP10225, GTB12001)
- Ministero della Salute
- Lundbeckfonden (R165-2013-15982)
- Associazione Italiana per la Ricerca sul Cancro (PRIN 2009, IG-2010)
- Università degli Studi di Roma Tor Vergata
- Royal Veterinary College
- Biotechnology and Biological Sciences Research Council (BB/I013695/1)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- AMBRA1, mitophagy, LC3-interacting region, Parkin, p62, autophagy regulation, Bcl-2, mitochondrial outer membrane, neurodegenerative diseases
- MeSH terms
- Sequestosome-1 Protein, Animals, Autophagy, Heat-Shock Proteins, HeLa Cells, Humans, Mice, Transgenic, Microtubule-Associated Proteins, Mitochondria, Transfection, Neurodegenerative Diseases, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Mice, HEK293 Cells
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