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Fig. 4 | Cell Communication and Signaling

Fig. 4

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

Fig. 4

Impact of AV level on homogeneous mitochondrial population. a Imagestream X analysis of normalized GFP-LC3 AV intensities in cell populations under basal, activated and Bafilomycin A1 (Baf)-inhibited autophagy conditions for 3 h. Autophagic flux is reported as fold change, calculated from mean normalized steady state and cumulative (Baf-treated) GFP-LC3 AV intensities. (left) Experiments under conditions of autophagy activation by nutrient deprivation (ND), and ND with lysosomal inhibitor Baf (100 nM) treatment in cell lines: Capan1 and Panc1 (pancreatic cancer), HPDE (non-tumorgenic pancreatic epithelial), HeLa (ovarian cancer), MCF7 (breast cancer), MCF10A (non-tumorgenic breast epithelial). (right) Autophagy activation via treatment with mTOR inhibitor RAD001 (100 nM), and in RAD001 combined with Baf under conditions of full medium (FM). b Model simulations using similar fold changes in AV content as in (a), in absence of tBid activation for homogeneous mitochondrial population. Results indicate mitophagy activation rate during an “activation” phase (light gray region), beginning (solid black line) of a “competition” phase (dark gray region), and point of mitophagy phenotype commitment (dashed red line) for all Bnip3 mutants. Spread in curves for each condition indicates cell-to-cell variability. c (left) Total number of mitochondria in a cell committed to mitophagy as final phenotype after tBid activation (at t = 5) and 20 % Bnip3 pre-activation with increasing AV levels for all three Bnip3 mutants and (middle) corresponding total cytochrome c release. (inset, bottom) Total cytochrome c release per time step by all mitochondria and (inset, top) total cumulative cytochrome c release for Bnip3 WT (d) Impact of delayed tBid activation (at t = 10) on cellular mitophagic response and total cytochrome c release for increasing AV levels. All simulated conditions had sample size of 50 runs with scatter points indicating a single run

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