Contents

πŸ“’ Kembro 2014

Complex oscillatory redox dynamics with signaling potential at the edge between normal and pathological mitochondrial function1

Sciwheel.

Introduction

  • mitochondria as a hub in the cellular metabolic network
  • The redox environment (RE) determines the relationship between mitochondrial respiration and ROS
  • The dependence of ROS on mitochondrial respiration involves two terms: production and emission; whereas the former depends on respiration (i.e., the rate of electron transport through the respiratory chain) the latter relies on the balance between the production and scavenging roles
  • glutathione (GSH) and thioredoxin (Trx) ROS scavenging: Duplication of antioxidant defense systems in multiple compartments can be an efficient salvage mechanism in response to oxidative bursts, and as a modulator of ROS dynamics.
  • Compartmentalization is relevant in the control of ROS levels and the redox environment

Materials and methods

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  • mitochondrial energetic-redox (ME-R) model with four main redox couples [NADH/NAD+, NADPH/NADP+, GSH/GSSG, Trx(SH)2/TrxSS].
  • All studies were performed using the parametric setting with which the ME-R model was able to simulate different experimental situations
  • the Shunt was utilized as the bifurcation parameter at fixed concentrations of mitochondrial superoxide dismutase (Mn SOD) and extra-mitochondrial superoxide dismutase (Cu,Zn SOD).

Results

Extra-mitochondrial SOD determines oscillatory mitochondrial dynamics at the edge between functional and pathological behavior

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  • detailed exploration of mitochondrial redox (NADH) behavior as a function of SODs and Shunt using stability analysis
  • This oscillatory region becomes more confined as the antioxidant capacity of Cu, Zn SOD in the extra-mitochondrial compartment is enhanced
  • The bifurcation diagrams evolve from smoother to steeper S-shapes depending on the concentration of Cu, Zn SOD
  • the thin line connecting upper and lower branches of steady states in the bifurcation diagrams from Figure ​Figure22 exhibits both an unstable focus and a stable limit cycle

Complex oscillatory behavior at the edge of normal and pathological mitochondrial behavior

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  • an increase in the concentration of Cu, Zn SOD or Mn SOD or decrease in shunt => lower frequency oscillations

  • model simulations can reproduce the frequency of experimentally observed oscillations (~0.01 Hz, equivalent to a period of ~100 s) for at least four distinct parametric combinations

  • dependence of their amplitude vs. frequency. Inverse relationship. An increase in the frequency (corresponding to a decrease in CuZnSOD concentration shown in Figure ​Figure3A)3A) results in a decrease in the amplitude of the oscillations https://www.frontiersin.org/files/Articles/93653/fphys-05-00257-HTML/image_m/fphys-05-00257-g004.jpg

  • Under oxidative stress (Shunt = 4%), increasing mitochondrial MnSOD at low cytosolic Cu, Zn SOD results not only in changes in frequency and amplitude, but also in the complexity of the oscillatory waveform https://www.frontiersin.org/files/Articles/93653/fphys-05-00257-HTML/image_m/fphys-05-00257-g005.jpg

  • power spectral analysis: high sharp peak in the frequency domain was observed at ~0.035 Hz, followed by harmonics of slightly lower values: similar to a Dirac comb (spike train)

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Phase space 3D projections of the state variables H2O2i, ΔΨm and succinate

  • Result: the complexity of the oscillations waveform is enhanced as a function of increasing oxidative stress conditions.

Discussion

  • The main contribution of the present work is to show that the interplay of Cu, Zn SOD (SOD1) and Mn SOD (SOD2) activities determines the appearance of complex oscillations in mitochondrial dynamics
  • none of the other parameters from our model, apart from the three studied herein, were capable of eliciting oscillatory behavior.
  • Experiments: SOD concentrations, values reported are ~0.5 ΞΌM. ROS reportedly ranged from 0.15 to 11% of the O2 consumption flux
  • The emergence of complex oscillatory behavior within the β€œedge” region. Oscillations occurred in a restricted region of the parametric space defined by the SODs and ROS production in the respiratory chain. https://www.frontiersin.org/files/Articles/93653/fphys-05-00257-HTML/image_m/fphys-05-00257-g007.jpg
  • the higher the antioxidant capacity of the periplasm-cytoplasm, the larger the parametric space compatible with functional behavior. As a result when Cu, Zn SOD concentration increases, the ability of the two compartments to tolerate higher mitochondrial ROS production is enhanced, even at low concentrations of MnSOD.
  • The inverse amplitude vs. frequency relationship was demonstrated previously (Aon et al., 2006) and is confirmed by the present, more elaborate, ME-R model.
  • Specifically, the 3D phase space projection of the dynamics of H2O2 released as a function of other energetic variables (ΔΨm, succinate) demonstrates the dynamic-functional interrelationships between processes occurring within the same time scale (seconds).

Reference


  1. Kembro JM, Cortassa S, Aon MA. Complex oscillatory redox dynamics with signaling potential at the edge between normal and pathological mitochondrial function. Front Physiol. 2014;5:257. Published 2014 Jul 8. doi:10.3389/fphys.2014.00257 ↩︎