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Review
. 2023 Oct 17;12(10):1873.
doi: 10.3390/antiox12101873.

Redox-Mediated Rewiring of Signalling Pathways: The Role of a Cellular Clock in Brain Health and Disease

Filip Vujovic  1   2 , Claire E Shepherd  3 , Paul K Witting  4 , Neil Hunter  1 , Ramin M Farahani  1   2
Affiliations
Review

Redox-Mediated Rewiring of Signalling Pathways: The Role of a Cellular Clock in Brain Health and Disease

Filip Vujovic et al. Antioxidants (Basel). .

Abstract

Metazoan signalling pathways can be rewired to dampen or amplify the rate of events, such as those that occur in development and aging. Given that a linear network topology restricts the capacity to rewire signalling pathways, such scalability of the pace of biological events suggests the existence of programmable non-linear elements in the underlying signalling pathways. Here, we review the network topology of key signalling pathways with a focus on redox-sensitive proteins, including PTEN and Ras GTPase, that reshape the connectivity profile of signalling pathways in response to an altered redox state. While this network-level impact of redox is achieved by the modulation of individual redox-sensitive proteins, it is the population by these proteins of critical nodes in a network topology of signal transduction pathways that amplifies the impact of redox-mediated reprogramming. We propose that redox-mediated rewiring is essential to regulate the rate of transmission of biological signals, giving rise to a programmable cellular clock that orchestrates the pace of biological phenomena such as development and aging. We further review the evidence that an aberrant redox-mediated modulation of output of the cellular clock contributes to the emergence of pathological conditions affecting the human brain.

Keywords: brain development; cellular clock; mitochondria; neurodegenerative disorders; redox.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Network motifs utilised in the cellular clock. In an I1-FFL (right), competing inputs from an activator (D) and an inhibitor (B) elicited downstream to a common activator (A) generate a pulsed signalling output (C) as opposed to a linear flow of information (C). Multiple programmable I1-FFLs can be linked via AND gates to control the pace of complex biological phenomena (X, X’, Y, Z represent signalling mediators). Inhibition of the inhibitory arm of I1-FFLs by various cues (e.g., mitochondrial ROS) accelerates the signalling outcome proportional to the number on I1-FFLs linked together in series.
Figure 2
Figure 2
Redox-mediated regulation of I1-FFLPI3K/Ras. (A) The close-up view of H-Ras (PDB: 121P) shows contribution of the redox-sensitive Cys-118 to the GTP binding pocket of the protein. (B) Evolutionary conservation of the redox-sensitive Cys-118 (n = 124 species within the subphylum Vertebrata). (C) A simplified presentation of the signals invoked downstream to the receptor tyrosine kinases (RTKs). Note the opposing impacts PI3k and Ras on Raf-1 leading to the emergence of an I1-FFL. In this I1-FFL topology, while RTK-mediated activation of Ras (via Grb2/SOS) positively regulates Raf, RTK/PI3K-mediated activation of PKB/Akt inhibits it. (D) Redox-mediated activation of Ras and subcellular localisation of Ras into redox-active endosomes resolves the I1-FFLPI3K/Ras.
Figure 3
Figure 3
Redox-mediated regulation of I1-FFLPI3K/PTEN. (A) A simplified presentation of the PI3K and PTEN signals invoked downstream to the activation of RTKs. (B) The close-up view of PTEN (AlphaFoldDB: F6KD01) shows the redox-sensitive Cys-71 and Cys-124. (C) Evolutionary conservation of the redox-sensitive Cys-71 and Cys-124 of PTEN (n = 124 species within the subphylum vertebrata). (D). Redox-mediated resolution of the I1-FFLPI3K/PTEN.
Figure 4
Figure 4
An elemental blueprint for the proposed redox-sensitive cellular clock. The main contributors to a cellular clock are I1-FFLPI3K/PTEN, I1-FFLPI3K/Ras and I1-FFLRas/Rap1 connected via AND gates. Reprogramming of key redox-sensitive proteins (marked by green circles) resolves the I1-FFLs leading to amplification of downstream signalling outputs. Other minor contributing I1-FFLs downstream to Ras signalling are also reprogrammed in a redox-dependent manner (right). While Rap-induced Raf-1 stabilises c-Myc, sequestration of β-catenin to Ras-induced formation of the junctional complexes reduces β-catenin-mediated trans-activation of c-Myc locus. Redox-mediated disassembly of the junctional complexes resolves this I1-FFL. The outcome of redox-mediated reprogramming of linked I1-FFLs is activation of the pro-anabolic master regulator c-Myc and mTOR-dependent inhibition of catabolic activity leading to accelerated progression of biological phenomena (e.g., cell cycle).
Figure 5
Figure 5
Redox-mediated reprogramming of cellular clock in neurodegenerative disorders. The synaptic transmission of signals, the stability of Tau protein and the associated microtubules and the differentiation propensity of neural progenitor cells (NPC) are controlled by activity of redox-sensitive I1-FFLs (e.g., I1-FFLPI3K/PTEN). Hence, ROS generated as a consequence of an impaired electron transport chain (ETC) or hypoxia could potentially amplify the synaptic transmission, reduce tau solubility and trigger accelerated differentiation of neural progenitor cells leading to depletion of these cells.
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