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| Home > Publications database > Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis. > print |
| 001 | 126267 | ||
| 005 | 20240228140818.0 | ||
| 024 | 7 | _ | |a 10.1186/s12964-015-0115-9 |2 doi |
| 024 | 7 | _ | |a pmid:26253153 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC4528699 |2 pmc |
| 024 | 7 | _ | |a altmetric:4377661 |2 altmetric |
| 037 | _ | _ | |a DKFZ-2017-02382 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Choe, Sehyo Charley |0 P:(DE-HGF)0 |b 0 |e First author |
| 245 | _ | _ | |a Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis. |
| 260 | _ | _ | |a London |c 2015 |b Biomed Central |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1508404617_6998 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Mitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large-scale mitochondrial release of pro-apoptotic proteins activates caspase-dependent cell death, a limited release results in sub-lethal caspase activation which promotes tumorigenesis. Mitochondrial autophagy (mitophagy) targets dysfunctional mitochondria for degradation by lysosomes, and undergoes extensive crosstalk with apoptosis signaling, but its influence on apoptosis remains undetermined. The BH3-only protein Bnip3 integrates apoptosis and mitophagy signaling at different signaling domains. Bnip3 inhibits pro-survival Bcl2 members via its BH3 domain and activates mitophagy through its LC3 Interacting Region (LIR), which is responsible for binding to autophagosomes. Previously, we have shown that Bnip3-activated mitophagy prior to apoptosis induction can reduce mitochondrial activation of caspases, suggesting that a reduction to mitochondrial levels may be pro-survival. An outstanding question is whether organelle dynamics and/or recently discovered subcellular variations of protein levels responsible for both MOMP sensitivity and crosstalk between apoptosis and mitophagy can influence the cellular apoptosis decision event. To that end, here we undertook a systems biology analysis of mitophagy-apoptosis crosstalk at the level of cellular mitochondrial populations.Based on experimental findings, we developed a multi-scale, hybrid model with an individually adaptive mitochondrial population, whose actions are determined by protein levels, embedded in an agent-based model (ABM) for simulating subcellular dynamics and local feedback via reactive oxygen species signaling. Our model, supported by experimental evidence, identified an emergent regulatory structure within canonical apoptosis signaling. We show that the extent of mitophagy is determined by levels and spatial localization of autophagy capacity, and subcellular mitochondrial protein heterogeneities. Our model identifies mechanisms and conditions that alter the mitophagy decision within mitochondrial subpopulations to an extent sufficient to shape cellular outcome to apoptotic stimuli.Overall, our modeling approach provides means to suggest new experiments and implement findings at multiple scales in order to understand how network topologies and subcellular heterogeneities can influence signaling events at individual organelle level, and hence, determine the emergence of heterogeneity in cellular decisions due the actions of the collective intra-cellular population. |
| 536 | _ | _ | |a 312 - Functional and structural genomics (POF3-312) |0 G:(DE-HGF)POF3-312 |c POF3-312 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a BNIP3 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a BNip3 protein, mouse |2 NLM Chemicals |
| 650 | _ | 7 | |a Membrane Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Mitochondrial Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Proto-Oncogene Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Proto-Oncogene Proteins c-bcl-2 |2 NLM Chemicals |
| 650 | _ | 7 | |a Reactive Oxygen Species |2 NLM Chemicals |
| 650 | _ | 7 | |a Cytochromes c |0 9007-43-6 |2 NLM Chemicals |
| 700 | 1 | _ | |a Hamacher-Brady, Anne |0 P:(DE-He78)a8657988a6082d4d90605e15cd5d3302 |b 1 |u dkfz |
| 700 | 1 | _ | |a Brady, Nathan R |0 P:(DE-He78)5bf984e94f0a31773a103cd293e01f92 |b 2 |e Last author |u dkfz |
| 773 | _ | _ | |a 10.1186/s12964-015-0115-9 |g Vol. 13, no. 1, p. 37 |0 PERI:(DE-600)2126315-2 |n 1 |p 37 |t Cell communication and signaling |v 13 |y 2015 |x 1478-811X |
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