Oxidative eustress: On constant alert for redox homeostasis

Abstract

In the open metabolic system, redox-related signaling requires continuous monitoring and fine-tuning of the steady-state redox set point. The ongoing oxidative metabolism is a persistent challenge, denoted as oxidative eustress, which operates within a physiological range that has been called the 'Homeodynamic Space', the 'Goldilocks Zone' or the 'Golden Mean'. Spatiotemporal control of redox signaling is achieved by compartmentalized generation and removal of oxidants. The cellular landscape of H₂O₂, the major redox signaling molecule, is characterized by orders-of-magnitude concentration differences between organelles. This concentration pattern is mirrored by the pattern of oxidatively modified proteins, exemplified by S-glutathionylated proteins. The review presents the conceptual background for short-term (non-transcriptional) and longer-term (transcriptional/translational) homeostatic mechanisms of stress and stress responses. The redox set point is a variable moving target value, modulated by circadian rhythm and by external influence, summarily denoted as exposome, which includes nutrition and lifestyle factors. Emerging fields of cell-specific and tissue-specific redox regulation in physiological settings are briefly presented, including new insight into the role of oxidative eustress in embryonal development and lifespan, skeletal muscle and exercise, sleep-wake rhythm, and the function of the nervous system with aspects leading to psychobiology.

Keywords: Homeodynamics; Hydrogen peroxide; Oxidative stress; Redox biology; Redox landscape; Steady-state.

Fig. 1

Timeline of concepts of stress and adaptive stress responses. Mithridates VI [132] and Paracelsus [133] had early insight that the dose matters in deciding beneficial versus harmful outcome. Bernard's concept of the ‘milieu intérieur’ [26] received the name ‘homeostasis’ [134], and the Arndt-Schulz [135] rule received the name ‘hormesis’ [136]. The 20^th century brought the adaptive stress syndrome [24], heat shock response [137], oxidative stress [138], OxyR [139], allostasis [27], unfolded protein response [140], and the major mammalian master regulators NF-kB [141], HIF1 [142], and Nrf2/Keap1 [143]. From Ref. [20].

Fig. 2

‘Landscape’ of H₂O₂ across the cell. Generalized overview of estimated concentrations of H₂O₂ in subcellular spaces. Color code is from light blue (80 pM) to blue-green (4 nM), green (ca. 20 nM), brown (300 nM), and red (700 nM) (see Table 1 for References).

Fig. 3

Subcellular distribution of average protein S-glutathionylation (SSG occupancy) and total oxidation. Analysis of the redox proteome of macrophages. From Ref. [63].

Fig. 4

The redox proteome is organized through kinetically controlled thiol switches. From Ref. [3].

Fig. 5

Snapshot of diverse concentrations of H₂O₂ in various organs of the intact developing zebrafish embryo at 48 h post fertilization. 100 ng/μL of HyPer7 mRNA was injected in 1-cell stage zebrafish embryos. Scale bar, 100 μm. Embryo H₂O₂ imaging was performed essentially as described in Ref. [97]. H₂O₂ concentration is correlated to the YFP500/YFP420 excitation ratio of HyPer7. Photo taken by M. Thauvin, kindly provided by Prof. Sophie Vriz, Paris.