Contents

📒 Deoliveira 2016

A biophysical systems approach to identifying the pathways of acute and chronic doxorubicin mitochondrial cardiotoxicity1

Sciwheel

Introduction

  • Doxorubicin (DOX) presents dose dependent, cumulative and irreversible cardiotoxicity that can lead to cardiomyopathy and ultimately congestive heart failure, strongly associated to mitochondrial dysfunction
    • inhibit the electron transport chain (ETC) by binding to cardiolipin
    • redox cycling.
    • topoisomerase II poison and can form DNA adducts , which can damage the DNA and inhibit gene transcription and DNA replication
  • can form vicious cycles -> chronic irreversible toxicity

Method and Results

The model

https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g001&type=large https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g007&type=large

  • based on ETC-ROS and ME-R model with some modifications (please see suplement data)
  • TCA cycle, transporters, ROS production and scavenging systems and a detailed ETC representation
  • All simulations in this work consider that the mitochondria are in the presence of substrate and ADP (state 3)

ETC Inhibition

  • DOX binds onto cardiolipin in the IMM, IC50 values in the literature, with fitted Hill coefficients

Redox Cycling

  • In the complex I, as a multiplier to IF site ROS generation.
  • 7% increase in the superoxide concentration for 1mg/kg of DOX in rats (37mg/m2 in human, 5 to 30μM in mitochondria). 7% increase for 30μM of DOX in this model.

Damage to mtDNA

https://user-images.githubusercontent.com/40054455/86617155-6d48e380-bfe9-11ea-8fa0-e721a26ae269.png

  • mass action model for mtDNA damage and repair. mtDNA level is normalized (scaled).
  • expression of all proteins and enzymes encoded in mtDNA was considered to be scaled by the mtDNA concentration
  • mtDNA damage by [•OH] (hydroxyl radical, derived from other ROS) and DOX directly

Acute Effects

  • constant concentration of the drug and performing a simulation until the model reached a steady state. https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g002&type=large
  • For low drug concentrations, the ATP concentration and the membrane potential were only barely reduced
  • For high drug concentrations, mitochondrial function gradually deteriorate until a threshold is reached and the mitochondria completely collapse, with a complete loss of membrane potential and ATP concentration, a sharp increase in the ROS concentrations and a reduction in the O2 consumption to residual levels
  • Theshold: 210 μM https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g003&type=large
  • dynamic simulations: fast absorbtion (5 mins) and slow elimination (24 hrs)
  • For low doses, mitochondrial function is only marginally affected, but at high doses, some significant variations can be observed. Mitochondrial function deteriorates as the dose increases
  • these effects are always temporary and all quantities return to their baseline values after the drug is fully eliminated from the system

Chronic Effects

https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g004&type=large

  • Added mtDNA model. stable region 0.75-0.73. unstable < 0.73 (viscious cycle) https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g005&type=large
  • weekly doses of 1mg/kg of DOX, 30μM in the model.
  • direct mtDNA damage by DOX is the main pathway that triggers this vicious cycle, being responsible for over 75% of the mtDNA content reduction during the acute stages of DOX intoxication.

Cardioprotection Simulation

https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1005214.g006&type=large

  • Iron chelators to mitigate mtDNA damage and the loss of mtDNA content associated with DOX.
  • The simulations reproduced the setup of this in vivo experiment with rats
  • extending the chelating treatment to two of three times the duration of the DOX treatment might considerably increase the cardioprotection

Discussion

  • Redox cycling is the main contributor to acute increases in ROS concentrations at clinically relevant concentrations
  • ETC inhibition also showed negligible effects at clinically relevant concentrations, but more prominent @ lethal dose
  • redox cycling and ETC inhibition alone are not capable of generating any long term alterations in mitochondria function; mtDNA damage is necessary.
  • direct mtDNA damage by DOX is responsible for over 75% of the mtDNA content reduction during the acute stages of intoxication. ROS sustained the vicious cycle.
  • cardioprotective agent that has shown efficacy (partial protection)
  • extending the iron chelating therapy to time periods longer than the DOX treatment can enhance this protective property

Limitations

  • The repair systems of mtDNA are complex and still poorly understood
  • additional 15,000 simulations were performed, exhaustively exploring the space of potential parameter combinations
  • support the conclusion that direct damage to mtDNA by DOX is the main toxicity pathway responsible for triggering the vicious cycle
  • the expression of mtDNA encoded proteins was considered to be proportional to the mtDNA content
    • there could be delays between the mtDNA damage and the reduction in the density of mtDNA encoded proteins
  • do not take into account oxidative damage to any other structures or proteins

Reference


  1. De Oliveira BL, Niederer S. A biophysical systems approach to identifying the pathways of acute and chronic doxorubicin mitochondrial cardiotoxicity. PLoS Comput. Biol. 2016;12(11):e1005214. doi:10.1371/journal.pcbi.1005214. ↩︎