Threshold-Dependent Redox Network Rewiring Links Oxidative Stress to Chronic Inflammatory and Metabolic Disease: Mitochondrial ROS Amplification as a Tipping Point

Authors

  • Arafat Ahmad
  • Mohammad Arif
  • Samina Wasi
  • Nazia Hasan
  • Satyendra Kumar Sinha
  • Arati Gupta
  • Feroz Ahmad

DOI:

https://doi.org/10.63682/jns.v14i2.10074

Keywords:

Mitochondrial ROS, oxidative stress, redox signalling, redox network rewiring, tipping point, threshold dynamics, bistability, hysteresis, reverse electron transport (RET)

Abstract

No more as toxic products of aerobic metabolism Reactive oxygen species (ROS) are now viewed as signals that are compartmentalized and time-limited, and that signal ROS, and ROS particularly H2O2, regulates metabolic fluxes, immune activation and cell-fate pathways. In the meantime, oxidative stress is also getting identified as something more than more ROS, and this has been defined as either a perturbation of redox signalling and regulation, or an accretion of molecular damage when the production of oxidants becomes larger than its buffering capacity. According to this systemic strategy, it is this redoxome reprogramming threshold-dependent connection between oxidative stress and chronic inflammatory -metabolic disease that this review proposes as its central idea. Mitochondrial production of ROS (mtROS) is extremely sensitive to bioenergetics such as electron flux or Δp, NADH/NAD +, ubiquinone redox, access to substrates and O 2 (Figure 1 A ) and mitochondrial elimination of ROS is highly reliant on the NADPH-linked glutathione and thioredoxin/peroxiredoxin networks that may be saturated during chronic stress. We extrapolate mechanistic indications of nonlinearity and tipping-point mitochondrial behaviour by (i) burst-like amounts/production of mtROS in stationary likely defined respiratory conditions (e.g. reverse electron transport [RET] at Complex I or ROS-release at Complex III), (ii) the magnitude-enhancing positive feedback on a mitochondrial scale with subsequent stippling network propagation [depolarization waves, ROS-induced ROS release], and (iii) experimentally observed and modelled switch-like/mitigated mtRO We then add pathway level coupling, in which the pattern of connecting the nodes of the inflammatory and metabolic pathways -NF-kB, NLRP3 inflammasome, HIF-1α, insulin signalling by redox sensivity phosphatases (e.g., PTP1B/PTEN), AMPK energy sensing mTOR) - is to maintain steady disease states. Finally, we take into account methodological difficulties in quantification of compartmental redox states and the implications of successful interventions the necessity of spatial control of intervention, timing to proximate-to-threshold biomarker, and the requirement of restoration of redox-control mechanisms instead of nonselective disabling downstream oxidants..



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2025-02-25

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1.
Ahmad A, Arif M, Wasi S, Hasan N, Kumar Sinha S, Gupta A, et al. Threshold-Dependent Redox Network Rewiring Links Oxidative Stress to Chronic Inflammatory and Metabolic Disease: Mitochondrial ROS Amplification as a Tipping Point . J Neonatal Surg [Internet]. 2025 Feb. 25 [cited 2026 Mar. 17];14(2):353-67. Available from: https://jneonatalsurg.com/index.php/jns/article/view/10074

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Vol. 14 No. 2 (2025): Journal of Neonatal Surgery

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Original Article

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