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Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis.

Choe SC, Hamacher-Brady A, Brady NR - Cell Commun. Signal (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Systems Biology of Cell Death Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT

Background: 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.

Results: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Illustration of key findings. a Bnip3 dual-functionality and crosstalk between mitophagy and apoptosis pathways. b Bnip3 LIR activity determines interaction with LC3, and influences MOMP activation (and consequent cytochrome c release) (c) Level of mitophagy in a cell is dependent on mitochondrial autophagy potential (AV content), and spatial localization of autophagic vesicles (d) Subcellular heterogeneity at mitochondria, specifically proteins at crosstalk between both pathways, impact individual mitochondria response to stress and apoptosis signaling, resulting in emergence of sub-populations able to influence cell fate
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Fig8: Illustration of key findings. a Bnip3 dual-functionality and crosstalk between mitophagy and apoptosis pathways. b Bnip3 LIR activity determines interaction with LC3, and influences MOMP activation (and consequent cytochrome c release) (c) Level of mitophagy in a cell is dependent on mitochondrial autophagy potential (AV content), and spatial localization of autophagic vesicles (d) Subcellular heterogeneity at mitochondria, specifically proteins at crosstalk between both pathways, impact individual mitochondria response to stress and apoptosis signaling, resulting in emergence of sub-populations able to influence cell fate

Mentions: From our ODE model (Fig. 8a; Additional file 1: Figure S1) we can show how Bnip3 dual functionality shifts between BH3-mediated inhibition of Bcl2, thereby increasing activation of Bax by tBid, and LIR-mediated mitophagy, which reduces apoptotic signaling (Fig. 8b). Our model also proposes a simple explanation for how increased Bcl2/xL activity impacts apoptosis signaling by enhancing mitophagy: coincidently Bcl2/xL slows apoptosis induction, which reduces Bax mediated suppression of autophagy [27], and promotes mitophagy in the absence of apoptotic stimuli (Additional file 3: Figure S3) [14]. Several lines of evidence suggest that mitophagy-sensitized conditions occur under physiological and pathophysiological conditions. In vivo, Bcl-xL and Bnip3 expression is positively (and negatively) correlated in several disease and non-disease states (Additional file 14: Figure S14). Moreover, the autophagy receptor Bnip3L/Nix, a close homologue of Bnip3 [13], and Bcl-xL are co-upregulated during red blood cell (RBC) maturation [54]. We suggest that co-increase of Bnip3/Bnip3L and Bcl2/xL can alter the mitochondrial apoptotic pathway, providing autophagy capacity is sufficiently high. In addition, our modeling offers simple explanations for the impact of ROS through a positive feedback loop: Bnip3 requires ROS activation [43], and Bax activation generates ROS [30, 33–35]. Although this feedback is simplified, and discounts non-apoptotic ROS amplification [33, 34], an environmental decrease of ROS levels suppressed mitophagy induction (Additional file 7: Figure S7A-S7C), which is consistent with recent in vivo evidence that ROS suppression in the heart can impede mitophagy [32]. However, ROS signaling integrates with autophagy induction [31], alternative mitophagy modes [55], lysosomal death signaling [56] and apoptosis [30], and therefore further work is required to better elucidate its role in regulating additional pathway crosstalk.Fig. 8


Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis.

Choe SC, Hamacher-Brady A, Brady NR - Cell Commun. Signal (2015)

Illustration of key findings. a Bnip3 dual-functionality and crosstalk between mitophagy and apoptosis pathways. b Bnip3 LIR activity determines interaction with LC3, and influences MOMP activation (and consequent cytochrome c release) (c) Level of mitophagy in a cell is dependent on mitochondrial autophagy potential (AV content), and spatial localization of autophagic vesicles (d) Subcellular heterogeneity at mitochondria, specifically proteins at crosstalk between both pathways, impact individual mitochondria response to stress and apoptosis signaling, resulting in emergence of sub-populations able to influence cell fate
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4528699&req=5

Fig8: Illustration of key findings. a Bnip3 dual-functionality and crosstalk between mitophagy and apoptosis pathways. b Bnip3 LIR activity determines interaction with LC3, and influences MOMP activation (and consequent cytochrome c release) (c) Level of mitophagy in a cell is dependent on mitochondrial autophagy potential (AV content), and spatial localization of autophagic vesicles (d) Subcellular heterogeneity at mitochondria, specifically proteins at crosstalk between both pathways, impact individual mitochondria response to stress and apoptosis signaling, resulting in emergence of sub-populations able to influence cell fate
Mentions: From our ODE model (Fig. 8a; Additional file 1: Figure S1) we can show how Bnip3 dual functionality shifts between BH3-mediated inhibition of Bcl2, thereby increasing activation of Bax by tBid, and LIR-mediated mitophagy, which reduces apoptotic signaling (Fig. 8b). Our model also proposes a simple explanation for how increased Bcl2/xL activity impacts apoptosis signaling by enhancing mitophagy: coincidently Bcl2/xL slows apoptosis induction, which reduces Bax mediated suppression of autophagy [27], and promotes mitophagy in the absence of apoptotic stimuli (Additional file 3: Figure S3) [14]. Several lines of evidence suggest that mitophagy-sensitized conditions occur under physiological and pathophysiological conditions. In vivo, Bcl-xL and Bnip3 expression is positively (and negatively) correlated in several disease and non-disease states (Additional file 14: Figure S14). Moreover, the autophagy receptor Bnip3L/Nix, a close homologue of Bnip3 [13], and Bcl-xL are co-upregulated during red blood cell (RBC) maturation [54]. We suggest that co-increase of Bnip3/Bnip3L and Bcl2/xL can alter the mitochondrial apoptotic pathway, providing autophagy capacity is sufficiently high. In addition, our modeling offers simple explanations for the impact of ROS through a positive feedback loop: Bnip3 requires ROS activation [43], and Bax activation generates ROS [30, 33–35]. Although this feedback is simplified, and discounts non-apoptotic ROS amplification [33, 34], an environmental decrease of ROS levels suppressed mitophagy induction (Additional file 7: Figure S7A-S7C), which is consistent with recent in vivo evidence that ROS suppression in the heart can impede mitophagy [32]. However, ROS signaling integrates with autophagy induction [31], alternative mitophagy modes [55], lysosomal death signaling [56] and apoptosis [30], and therefore further work is required to better elucidate its role in regulating additional pathway crosstalk.Fig. 8

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Systems Biology of Cell Death Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT

Background: 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.

Results: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus