Abstract
The time-keeping properties bestowed by oscillatory behavior on functional rhythms represent an evolutionarily conserved trait in living systems. Mitochondrial networks function as timekeepers maximizing energetic output while tuning reactive oxygen species (ROS) within physiological levels compatible with signaling. In this work, we explore the potential for timekeeping functions dependent on mitochondrial dynamics with the validated two-compartment mitochondrial energetic-redox (ME-R) computational model, that takes into account (a) four main redox couples [NADH, NADPH, GSH, Trx(SH)2], (b) scavenging systems (glutathione, thioredoxin, SOD, catalase) distributed in matrix and extra-matrix compartments, and (c) transport of ROS species between them. Herein, we describe that the ME-R model can exhibit highly complex oscillatory dynamics in energetic/redox variables and ROS species, consisting of at least five frequencies with modulated amplitudes and period according to power spectral analysis. By stability analysis we describe that the extent of steady state—as against complex oscillatory behavior—was dependent upon the abundance of Mn and Cu, Zn SODs, and their interplay with ROS production in the respiratory chain. Large parametric regions corresponding to oscillatory dynamics of increasingly complex waveforms were obtained at low Cu, Zn SOD concentration as a function of Mn SOD. This oscillatory domain was greatly reduced at higher levels of Cu, Zn SOD. Interestingly, the realm of complex oscillations was located at the edge between normal and pathological mitochondrial energetic behavior, and was characterized by oxidative stress. We conclude that complex oscillatory dynamics could represent a frequency- and amplitude-modulated H2O2 signaling mechanism that arises under intense oxidative stress. By modulating SOD, cells could have evolved an adaptive compromise between relative constancy and the flexibility required under stressful redox/energetic conditions.
Highlights
Poised at the convergence of most catabolic and anabolic pathways, mitochondria are at the center of heterotrophic aerobic life, representing a hub in the cellular metabolic network (Aon et al, 2007a; Aon and Cortassa, 2012; Cortassa and Aon, 2013; Kembro et al, 2014)
We explore the potential for timekeeping functions dependent on mitochondrial dynamics with the validated two-compartment mitochondrial energetic-redox (ME-R) computational model, that takes into account (a) four main redox couples [NADH, NADPH, GSH, Trx(SH)2], (b) scavenging systems distributed in matrix and extra-matrix compartments, and (c) transport of reactive oxygen species (ROS) species between them
We investigated the dependence of the mitochondrial dynamic behavior as a function of three key model parameters
Summary
Poised at the convergence of most catabolic and anabolic pathways, mitochondria are at the center of heterotrophic aerobic life, representing a hub in the cellular metabolic network (Aon et al, 2007a; Aon and Cortassa, 2012; Cortassa and Aon, 2013; Kembro et al, 2014). The energetic functions performed by mitochondria face the unavoidable redox hurdle of handling huge amounts of O2 while keeping their own as well as the cellular redox environment. Mitochondria produce ∼85–90% of cellular reactive oxygen species (ROS) (Chance et al, 1979; Shigenaga et al, 1994; Balaban et al, 2005), while supplying the bulk of ATP demanded by the organs in the human body. The heart consumes proportionately most of the O2 on a specific basis with respect to the whole human body (Rolfe and Brown, 1997) thereby becoming especially vulnerable to oxidative damage. Considered an unavoidable and dangerous byproduct of oxidative phosphorylation (OxPhos), more recently we have become aware of the crucial role played by ROS signaling in key cellular functions.
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