The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Modulation of Serines 17 and 24 in the LC3-interacting Region of Bnip3 Determines Pro-survival Mitophagy versus Apoptosis
Open accessAbstract
BH3-only proteins integrate apoptosis and autophagy pathways, yet regulation and functional consequences of pathway cross-talk are not fully resolved. The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. Here we report that phosphorylation of serine residues 17 and 24 flanking the Bnip3 LIR promotes binding to specific Atg8 members LC3B and GATE-16. Using quantitative multispectral image-based flow cytometry, we demonstrate that enhancing Bnip3-Atg8 interactions via phosphorylation-mimicked LIR mutations increased mitochondrial sequestration, lysosomal delivery, and degradation. Importantly, mitochondria were targeted by mitophagy prior to cytochrome c release, resulting in reduced cellular cytochrome c release capacity. Intriguingly, pro-survival Bcl-x L positively regulated Bnip3 binding to LC3B, sequestration, and mitochondrial autophagy, further supporting an anti-apoptotic role for Bnip3-induced mitophagy. The ensemble of these results demonstrates that the phosphorylation state of the Bnip3 LIR signals either the induction of apoptosis or pro-survival mitophagy. Background: Bnip3 is both a pro-apoptotic BH3-only protein and a mitochondrial autophagy receptor. Results: Serine phosphorylation of the Bnip3 LC3-interacting region (LIR) increased binding to Atg8 members and consequently mitophagy, in a manner positively regulated by Bcl-x L . Conclusion: The Bnip3 LIR activity state determines either pro-survival mitophagy or mitochondrial apoptosis. Significance: Bnip3-induced mitophagy is serine kinase-regulated and thus a targetable pathway.
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Citations
Cites
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
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LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
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Nix is a selective autophagy receptor for mitochondrial clearance
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“The mitochondrial uncoupler CCCP, which collapses the mitochondrial membrane potential, enhances Nix-driven mitophagy in a LIR-dependent manner (23).”
BackgroundMethodInfluentialEssential role for Nix in autophagic maturation of erythroid cells
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Role of BNIP3 and NIX in cell death, autophagy, and mitophagy
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Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy
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Self-citationMitochondrial Pruning by Nix and BNip3: An Essential Function for Cardiac-Expressed Death Factors
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Cited by
Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance
Pickles, S., Vigié, P., & Youle, R. J. (2018) · Current Biology · doi:10.1016/j.cub.2018.01.004 · Cited by 2,081
Cargo recognition and trafficking in selective autophagy
Stolz, A., Ernst, A., & Dikic, I. (2014) · Nature Cell Biology · doi:10.1038/ncb2979 · Cited by 1,207
Rogov, V., Dötsch, V., Johansen, T., & Kirkin, V. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.014 · Cited by 992
Autophagy at the crossroads of catabolism and anabolism
Kaur, J., & Debnath, J. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4024 · Cited by 991
Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans
Palikaras, K., Lionaki, E., & Tavernarakis, N. (2015) · Nature · doi:10.1038/nature14300 · Cited by 770
Metadata
- Authors
- Zhu, Y., Massen, S., Terenzio, M., Lang, V., Chen-Lindner, S., Eils, R., Novak, I., Dikic, I., Hamacher-Brady, A., & Brady, N. R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 288
- Issue
- 2
- Pages
- 1099-1113
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2144450295
- Cited by
- 488
- References
- 13
- FWCI
- 12.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Zhu, Y., Massen, S., Terenzio, M., Lang, V., Chen-Lindner, S., Eils, R., Novak, I., Dikic, I., Hamacher-Brady, A., & Brady, N. R. (2013). Modulation of Serines 17 and 24 in the LC3-interacting Region of Bnip3 Determines Pro-survival Mitophagy versus Apoptosis. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m112.399345
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