Fig 1.
DOX could trigger vicious cycles that lead to progressive mitochondrial dysfunction.
The dashed arrows represent the acute effects of DOX. The solid arrows represent the interactions between elements while the gray arrows represent the potential vicious cycles that could be formed.
Fig 2.
Normalized variation of different indices of mitochondrial function with respect to acute concentrations of DOX in the mitochondria.
A constant concentration of DOX was used as an input and simulations were performed until steady state. It is possible to compare the effects of ETC inhibition, redox cycling (RC) and both combined.
Fig 3.
Normalized dynamic variation of mitochondrial function to different doses of DOX.
Time varying concentrations of DOX following the drug’s pharmacokinetics were used as an input. The resulting variation in different measurements of mitochondrial function can be observed.
Fig 4.
Effects of the variation of the mtDNA content in mitochondrial function.
It is possible to observe a bifurcation point when the mtDNA content is equal to 0.73. For mtDNA contents higher than 0.73 the mitochondria are in a stable condition and recovers to baseline over time. For a mtDNA content lower than 0.73, the mitochondria are unstable and its function will perpetually deteriorate until collapse.
Fig 5.
Predicted effects of the treatment with weekly doses of 30μM of DOX.
One dose is not sufficient to trigger the vicious cycle responsible for chronic cardiotoxicity. With four doses, the vicious cycle is triggered but the progression is slow. With seven doses, a faster progression is observed and the predicted reduction in mtDNA content is within the error of the experimental data used to fit the model’s parameters [15]. With ten doses a fast deterioration and collapse in mitochondrial function is observed.
Fig 6.
Predicted effects of the treatment with seven weekly doses of 24μM of DOX with and without co-treatment with iron chelators.
In the simulation without iron chelator co-treatment (blue), the predicted reduction in the mtDNA content agrees with the experimental data, which was used in the fitting of the model’s parameters [21]. The model was capable of capturing the cardioprotective feature of iron chelator co-treatment (green), and the predicted reduction in the mtDNA content also agrees with experimental data [21]. The model predicts that extending the iron chelation therapy by double (red) or triple (yellow) the duration of the DOX treatment can enhance cardioprotection.
Fig 7.
A schematic of the mitochondrial model used.
The expressions of ATP synthase and Complexes I, III and IV of the ETC are scaled by the mtDNA content as these structures are encoded at mtDNA. The acute effects of DOX are highlighted in red.