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Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.

Huber HJ, Dussmann H, Kilbride SM, Rehm M, Prehn JH - Mol. Syst. Biol. (2011)

Bottom Line: In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨ(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease.ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨ(m).Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.

View Article: PubMed Central - PubMed

Affiliation: Systems Biology Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.

ABSTRACT
Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨ(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨ(m). However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.

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Computational model of mitochondrial bioenergetics during cyt-c release and apoptosis. Interactions and transport processes between the mitochondrial matrix (‘Matrix'), mitochondrial intermembrane space (‘IMS') and the cytosol (‘Cytosol'). Roman numbers indicate single-cell processes that influence mitochondrial bioenergetics: (I) model of mitochondrial apoptosis (according to Rehm et al, 2006) that activates caspase-3 upon cyt-c release; (II) cytosolic ATP production and consumption; (III) active caspase-3 cleaving complex I/II; (IV) cyt-c release. Metabolite and ion fluxes of mitochondrial bioenergetics are given by Arabic numbers: (1) input function (NADH/NAD disequilibrium=45.8:1); (2–4) respiration complexes I/II (considered together), III and IV; (5) ATP synthase; (6) adenosine nucleotide transferase (ANT); (7) mitochondrial inner membrane proton leaks; (8) passive transport of adenosine phosphates and anorganic phosphate trough the outer mitochondrial membrane; (9) phosphate–proton cotransport and (10) proton–potassium antiport.
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f2: Computational model of mitochondrial bioenergetics during cyt-c release and apoptosis. Interactions and transport processes between the mitochondrial matrix (‘Matrix'), mitochondrial intermembrane space (‘IMS') and the cytosol (‘Cytosol'). Roman numbers indicate single-cell processes that influence mitochondrial bioenergetics: (I) model of mitochondrial apoptosis (according to Rehm et al, 2006) that activates caspase-3 upon cyt-c release; (II) cytosolic ATP production and consumption; (III) active caspase-3 cleaving complex I/II; (IV) cyt-c release. Metabolite and ion fluxes of mitochondrial bioenergetics are given by Arabic numbers: (1) input function (NADH/NAD disequilibrium=45.8:1); (2–4) respiration complexes I/II (considered together), III and IV; (5) ATP synthase; (6) adenosine nucleotide transferase (ANT); (7) mitochondrial inner membrane proton leaks; (8) passive transport of adenosine phosphates and anorganic phosphate trough the outer mitochondrial membrane; (9) phosphate–proton cotransport and (10) proton–potassium antiport.

Mentions: We devised our model with gradually increasing complexity and thus started with the widely studied experimental system of isolated mitochondria. We assembled the network of electrochemical reactions consisting of mitochondrial respiration, ATP production and ion transport, and used a fixed NADH/NAD disequilibrium as model input (Figure 2, and Materials and methods section). By Monte-Carlo screening, we calibrated the model into three scenarios that have been experimentally well described. These were (i) ATP producing (‘state-3') mitochondria in buffered medium of an ATP/ADP ratio of 3:1 (75% ATP, 25% ADP), (ii) non-ATP producing, resting-state (‘state-4') mitochondria (100% ATP, no ADP) and (iii) a situation where we considered mitochondria to change from state-3 to state-4 (Supplementary Figure 1A). Further details on the model construction and its calibration can be found in Supplementary Text I.


Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.

Huber HJ, Dussmann H, Kilbride SM, Rehm M, Prehn JH - Mol. Syst. Biol. (2011)

Computational model of mitochondrial bioenergetics during cyt-c release and apoptosis. Interactions and transport processes between the mitochondrial matrix (‘Matrix'), mitochondrial intermembrane space (‘IMS') and the cytosol (‘Cytosol'). Roman numbers indicate single-cell processes that influence mitochondrial bioenergetics: (I) model of mitochondrial apoptosis (according to Rehm et al, 2006) that activates caspase-3 upon cyt-c release; (II) cytosolic ATP production and consumption; (III) active caspase-3 cleaving complex I/II; (IV) cyt-c release. Metabolite and ion fluxes of mitochondrial bioenergetics are given by Arabic numbers: (1) input function (NADH/NAD disequilibrium=45.8:1); (2–4) respiration complexes I/II (considered together), III and IV; (5) ATP synthase; (6) adenosine nucleotide transferase (ANT); (7) mitochondrial inner membrane proton leaks; (8) passive transport of adenosine phosphates and anorganic phosphate trough the outer mitochondrial membrane; (9) phosphate–proton cotransport and (10) proton–potassium antiport.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094064&req=5

f2: Computational model of mitochondrial bioenergetics during cyt-c release and apoptosis. Interactions and transport processes between the mitochondrial matrix (‘Matrix'), mitochondrial intermembrane space (‘IMS') and the cytosol (‘Cytosol'). Roman numbers indicate single-cell processes that influence mitochondrial bioenergetics: (I) model of mitochondrial apoptosis (according to Rehm et al, 2006) that activates caspase-3 upon cyt-c release; (II) cytosolic ATP production and consumption; (III) active caspase-3 cleaving complex I/II; (IV) cyt-c release. Metabolite and ion fluxes of mitochondrial bioenergetics are given by Arabic numbers: (1) input function (NADH/NAD disequilibrium=45.8:1); (2–4) respiration complexes I/II (considered together), III and IV; (5) ATP synthase; (6) adenosine nucleotide transferase (ANT); (7) mitochondrial inner membrane proton leaks; (8) passive transport of adenosine phosphates and anorganic phosphate trough the outer mitochondrial membrane; (9) phosphate–proton cotransport and (10) proton–potassium antiport.
Mentions: We devised our model with gradually increasing complexity and thus started with the widely studied experimental system of isolated mitochondria. We assembled the network of electrochemical reactions consisting of mitochondrial respiration, ATP production and ion transport, and used a fixed NADH/NAD disequilibrium as model input (Figure 2, and Materials and methods section). By Monte-Carlo screening, we calibrated the model into three scenarios that have been experimentally well described. These were (i) ATP producing (‘state-3') mitochondria in buffered medium of an ATP/ADP ratio of 3:1 (75% ATP, 25% ADP), (ii) non-ATP producing, resting-state (‘state-4') mitochondria (100% ATP, no ADP) and (iii) a situation where we considered mitochondria to change from state-3 to state-4 (Supplementary Figure 1A). Further details on the model construction and its calibration can be found in Supplementary Text I.

Bottom Line: In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨ(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease.ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨ(m).Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.

View Article: PubMed Central - PubMed

Affiliation: Systems Biology Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.

ABSTRACT
Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨ(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨ(m). However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.

Show MeSH
Related in: MedlinePlus