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Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease.

ABSTRACT: Hydrogen peroxide (H2O2), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipid metabolism, also serve as hubs in the H2O2 signaling network. We first briefly introduce the basic concepts of how H2O2 can drive cellular signaling events. Next, we outline the peroxisomal enzyme systems involved in H2O2 metabolism in mammals and reflect on how this oxidant can permeate across the organellar membrane. In addition, we provide an up-to-date overview of molecular targets and biological processes that can be affected by changes in peroxisomal H2O2 metabolism. Where possible, emphasis is placed on the molecular mechanisms and factors involved. From the data presented, it is clear that there are still numerous gaps in our knowledge. Therefore, gaining more insight into how peroxisomes are integrated in the cellular H2O2 signaling network is of key importance to unravel the precise role of peroxisomal H2O2 production and scavenging in normal and pathological conditions.

SUBMITTER: Lismont C

PROVIDER: S-EPMC6695606 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease.

Lismont Celien C Revenco Iulia I Fransen Marc M

International journal of molecular sciences 20190726 15

Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipi ...[more]

PMID: 31357514

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Project description:The regulatory mechanisms by which hydrogen peroxide (H2O2) modulates the activity of transcription factors in bacteria (OxyR and PerR), lower eukaryotes (Yap1, Maf1, Hsf1 and Msn2/4) and mammalian cells (AP-1, NRF2, CREB, HSF1, HIF-1, TP53, NF-κB, NOTCH, SP1 and SCREB-1) are reviewed. The complexity of regulatory networks increases throughout the phylogenetic tree, reaching a high level of complexity in mammalians. Multiple H2O2 sensors and pathways are triggered converging in the regulation of transcription factors at several levels: (1) synthesis of the transcription factor by upregulating transcription or increasing both mRNA stability and translation; (ii) stability of the transcription factor by decreasing its association with the ubiquitin E3 ligase complex or by inhibiting this complex; (iii) cytoplasm-nuclear traffic by exposing/masking nuclear localization signals, or by releasing the transcription factor from partners or from membrane anchors; and (iv) DNA binding and nuclear transactivation by modulating transcription factor affinity towards DNA, co-activators or repressors, and by targeting specific regions of chromatin to activate individual genes. We also discuss how H2O2 biological specificity results from diverse thiol protein sensors, with different reactivity of their sulfhydryl groups towards H2O2, being activated by different concentrations and times of exposure to H2O2. The specific regulation of local H2O2 concentrations is also crucial and results from H2O2 localized production and removal controlled by signals. Finally, we formulate equations to extract from typical experiments quantitative data concerning H2O2 reactivity with sensor molecules. Rate constants of 140 M(-1) s(-1) and ≥1.3 × 10(3) M(-1) s(-1) were estimated, respectively, for the reaction of H2O2 with KEAP1 and with an unknown target that mediates NRF2 protein synthesis. In conclusion, the multitude of H2O2 targets and mechanisms provides an opportunity for highly specific effects on gene regulation that depend on the cell type and on signals received from the cellular microenvironment.

Project description:Oxidants and canonical Wnt/?-catenin signaling have been shown to decrease cardiac Na(+) channel activity by suppressing NaV1.5 expression. Our aims are to determine if hydrogen peroxide (H2O2), one oxidant of reactive oxygen species (ROS), activates Wnt/?-catenin signaling and promotes ?-catenin nuclear activity, leading to suppression of NaV1.5 expression and if this suppression requires the interaction of ?-catenin with its nuclear partner, TCF4 (also called TCF7L2) to decrease SCN5a promoter activity. The results demonstrated that H2O2 increased ?-catenin, but not TCF4 nuclear localization determined by immunofluorescence without affecting total ?-catenin protein level. Furthermore, H2O2 exerted a dose- and time-dependent suppressive effect on NaV1.5 expression. RT-PCR and/or Western blot analyses revealed that overexpressing active form of ?-catenin or stabilizing ?-catenin by GSK-3? inhibitors, LiCl and Bio, suppressed NaV1.5 expression in HL-1 cells. In contrast, destabilization of ?-catenin by a constitutively active GSK-3? mutant (S9A) upregulated NaV1.5 expression. Whole-cell recording showed that LiCl significantly inhibited Na(+) channel activity in these cells. Using immunoprecipitation (IP), we showed that ?-catenin interacted with TCF4 indicating that ?-catenin as a co-transfactor, regulates NaV1.5 expression through TCF4. Analyses of the SCN5a promoter sequences among different species by using VISTA tools indicated that SCN5a promoter harbors TCF4 binding sites. Chromatin IP assays demonstrated that both ?-catenin and TCF4 were recruited in the SCN5a promoter, and regulated its activity. Luciferase promoter assays exhibited that ?-catenin inhibited the SCN5a promoter activity at a dose-dependent manner and this inhibition required TCF4. Small interfering (Si) RNA targeting ?-catenin significantly increased SCN5a promoter activity, leading to enhanced NaV1.5 expression. As expected, ?-catenin SiRNA prevents H2O2 suppressive effects on both SCN5a promoter activity and NaV1.5 expression. Our findings indicate that H2O2 inhibits NaV1.5 expression by activating the Wnt/?-catenin signaling and ?-catenin interacts with TCF4 to transcriptionally suppress cardiac NaV1.5 expression.

Dataset Information

Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease.

Publications

Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease.

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