ROS networks: designs, aging, Parkinson’s disease and precision therapies

Kolodkin, Alexey; Sharma, Raju Prasad; Colangelo, Anna Maria; Ignatenko, Andrew; Martorana, Francesca; Jennen, Danyel; Briedé, Jacco Jan; Brady, Nathan R.; Barberis, Matteo; Mondeel, Thierry D.G.A.; Papa, Michèle; Kumar, Vikas; Peters, Bernhard; Skupin, Alexander; Alberghina, Lilia; Balling, Rudi; Westerhoff, Hans V.

doi:10.1038/s41540-020-00150-w

Cited by 65 publications

(42 citation statements)

References 119 publications

(197 reference statements)

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“…OXPHOS also generates potentially toxic byproducts in the form of ROS, which, if not tightly regulated by antioxidant defenses, can disrupt mitochondrial physiology, damage DNA, modify protein functions, cause lipid peroxidation, and negatively influence signaling pathways including transcriptional regulation [ 47 , 48 ]. Hence, all mitochondrial processes can be impacted by unbalanced ROS regulation and may thus represent a common pathway/potential starting point for neurodegenerative diseases [ 49 , 50 , 51 ]. Neurons are characterized by a high metabolic demand and require reliable ATP synthesis for diverse neuro-communication functions including maintenance of resting membrane potential, neurotransmitter synthesis and release [ 52 ], thus, disruption of this process is particularly detrimental to neuron health and survival.…”

Section: Discoveries Of Mitochondria-specific Phenotypes In Ipsc Models Of Pdmentioning

confidence: 99%

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

Heger

Wise

Hees

et al. 2021

Cells

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Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson’s disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients’ somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.

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Section: Discoveries Of Mitochondria-specific Phenotypes In Ipsc Models Of Pdmentioning

confidence: 99%

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

Heger

Wise

Hees

et al. 2021

Cells

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“…Such a graph can be translated into mathematical equations that, when simulated, may lead to the identification of temporal mechanisms of GCBC differentiation. We have recently illustrated this for the network underlying cell cycle control and reactive oxygen species (ROS) production where we discovered new regulatory patterns (213,214). The intracellular regulatory network involved in the positive selection of GCBCs should be modeled similarly as a multi-component, temporally evolving dynamic system.…”

Section: Discussionmentioning

confidence: 99%

System-Level Scenarios for the Elucidation of T Cell-Mediated Germinal Center B Cell Differentiation

Verstegen¹,

Ubels²,

Westerhoff³

et al. 2021

Front. Immunol.

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Germinal center (GC) reactions are vital to the correct functioning of the adaptive immune system, through formation of high affinity, class switched antibodies. GCs are transient anatomical structures in secondary lymphoid organs where specific B cells, after recognition of antigen and with T cell help, undergo class switching. Subsequently, B cells cycle between zones of proliferation and somatic hypermutation and zones where renewed antigen acquisition and T cell help allows for selection of high affinity B cells (affinity maturation). Eventually GC B cells first differentiate into long-lived memory B cells (MBC) and finally into plasma cells (PC) that partially migrate to the bone marrow to encapsulate into long-lived survival niches. The regulation of GC reactions is a highly dynamically coordinated process that occurs between various cells and molecules that change in their signals. Here, we present a system-level perspective of T cell-mediated GC B cell differentiation, presenting and discussing the experimental and computational efforts on the regulation of the GCs. We aim to integrate Systems Biology with B cell biology, to advance elucidation of the regulation of high-affinity, class switched antibody formation, thus to shed light on the delicate functioning of the adaptive immune system. Specifically, we: i) review experimental findings of internal and external factors driving various GC dynamics, such as GC initiation, maturation and GCBC fate determination; ii) draw comparisons between experimental observations and mathematical modeling investigations; and iii) discuss and reflect on current strategies of modeling efforts, to elucidate B cell behavior during the GC tract. Finally, perspectives are specifically given on to the areas where a Systems Biology approach may be useful to predict novel GCBC-T cell interaction dynamics.

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“…Xue et al observed a basal NRF2 cytosol-nucleus oscillation behavior in cells with a period of about 2 hours for which they constructed a mathematical model of negative feedback through NRF2 phosphorylation and dephosphorylation without involving changes in the abundance (Xue et al 2015). Kolodkin et al has recently incorporated the KEAP1-NRF2 component into an ROS dynamic network to explore the design principles relevant to network-based therapies for Parkinson disease (Kolodkin et al 2020). Compared to the previous work, our present study provided a much more detailed analysis of the KEAP1-NRF2 module itself, which can be adapted and included in future systems-level models of antioxidant and detoxification responses.…”

Section: Discussionmentioning

confidence: 99%

“…Mathematical modeling plays a crucial role in understanding and predicting the quantitative behavior of redox pathways (Adimora et al 2010, Selvaggio et al 2018). Earlier modeling work including our own has included the KEAP1-NRF2 module in the larger context of the NRF2-mediated antioxidant response pathways (Zhang and Andersen 2007, Zhang et al 2009, Hamon et al 2014, Leclerc et al 2014, Khalil et al 2015, Xue et al 2015, Kolodkin et al 2020). However, in most of these studies the KEAP1-NRF2 module was treated as simplified degradation network motifs, yet the details of KEAP1-NRF2 interactions and especially the likely nonlinearity in signaling have not been explicitly and fully explored.…”

Section: Introductionmentioning

confidence: 99%

Mathematical Modeling Reveals Quantitative Properties of KEAP1-NRF2 Signaling

Liu

Zhang

2021

Preprint

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In response to oxidative and electrophilic stresses, cells launch an NRF2-mediated transcriptional antioxidant program. The activation of NRF2 depends on a redox sensor, KEAP1, which acts as an E3-ligase adaptor to promote the ubiquitination and degradation of NRF2. While a great deal has been learned about the molecular details of KEAP1, NRF2, and their interactions, the quantitative aspects of signal transfer conveyed by this redox duo are still largely unexplored. In the present study, we examined the signaling properties including response time, half-life, maximal activation, and response steepness (ultrasensitivity) of NRF2, through a suite of mathematical models. The models describe, with increasing complexity, the reversible binding of KEAP1 dimer and NRF2 via the ETGE and DLG motifs, NRF2 production, KEAP1-dependent and independent NRF2 degradation, and perturbations by different classes of NRF2 activators. Our simulations revealed that at the basal condition, NRF2 molecules are largely sequestered by KEAP1, with the KEAP1-NRF2 complex comparably distributed in either an ETGE-bound only (open) state or an ETGE and DLG dual-bound (closed) state, corresponding to the unlatched and latched configurations of the conceptual hinge-latch model. With two-step ETGE binding, the open and closed states operate in cycle mode at the basal condition and transition to equilibrium mode at stressed conditions. Class I-V, electrophilic NRF2 activators, which modify redox-sensing cysteine residues of KEAP1, shift the balance to a closed state that is unable to degrade NRF2 effectively. Total NRF2 has to accumulate to a level that nearly saturates existing KEAP1 to make sufficient free NRF2, therefore introducing a signaling delay. At the juncture of KEAP1 saturation, ultrasensitive NRF2 activation, i.e., a steep rise in the free NRF2 level, can occur through two simultaneous mechanisms, zero-order degradation mediated by DLG binding and protein sequestration (molecular titration) mediated by ETGE binding. These response characteristics of class I-V activators do not require disruption of DLG binding to unlatch the KEAP1-NRF2 complex. In comparison, class VI NRF2 activators, which directly compete with NRF2 for KEAP1 binding, can unlatch or even unhinge the KEAP1-NRF2 complex. This causes a shift to the open state of KEAP1-NRF2 complex and ultimately its complete dissociation, resulting in a fast release of free NRF2 followed by stabilization. Although class VI activators may induce free NRF2 to higher levels, ultrasensitivity is lost due to lower free KEAP1 and thus its NRF2-sequestering effect. Stress-induced NRF2 nuclear accumulation is enhanced when basal nuclear NRF2 turnover constitutes a small load to NRF2 production. Our simulation further demonstrated that optimal abundances of cytosolic and nuclear KEAP1 exist to maximize ultrasensitivity. In summary, by simulating the dual role of KEAP1 in repressing NRF2, i.e., sequestration and promoting degradation, our mathematical modeling provides key novel quantitative insights into the signaling properties of the crucial KEAP1-NRF2 module of the cellular antioxidant response pathway.

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ROS networks: designs, aging, Parkinson’s disease and precision therapies

Cited by 65 publications

References 119 publications

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

System-Level Scenarios for the Elucidation of T Cell-Mediated Germinal Center B Cell Differentiation

Mathematical Modeling Reveals Quantitative Properties of KEAP1-NRF2 Signaling

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