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@ARTICLE{Choe:126267,
      author       = {S. C. Choe$^*$ and A. Hamacher-Brady$^*$ and N. R.
                      Brady$^*$},
      title        = {{A}utophagy capacity and sub-mitochondrial heterogeneity
                      shape {B}nip3-induced mitophagy regulation of apoptosis.},
      journal      = {Cell communication and signaling},
      volume       = {13},
      number       = {1},
      issn         = {1478-811X},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2017-02382},
      pages        = {37},
      year         = {2015},
      abstract     = {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.},
      keywords     = {BNIP3 protein, human (NLM Chemicals) / BNip3 protein, mouse
                      (NLM Chemicals) / Membrane Proteins (NLM Chemicals) /
                      Mitochondrial Proteins (NLM Chemicals) / Proto-Oncogene
                      Proteins (NLM Chemicals) / Proto-Oncogene Proteins c-bcl-2
                      (NLM Chemicals) / Reactive Oxygen Species (NLM Chemicals) /
                      Cytochromes c (NLM Chemicals)},
      cin          = {B170 / B190},
      ddc          = {610},
      cid          = {I:(DE-He78)B170-20160331 / I:(DE-He78)B190-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26253153},
      pmc          = {pmc:PMC4528699},
      doi          = {10.1186/s12964-015-0115-9},
      url          = {https://inrepo02.dkfz.de/record/126267},
}