title: Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics.
abstract: Redox networks in the cell integrate signaling pathways that control metabolism, energetics, cell survival, and death. The physiological second messengers that modulate these pathways include nitric oxide, hydrogen peroxide, and electrophiles. Electrophiles are produced in the cell via both enzymatic and nonenzymatic lipid peroxidation and are also relatively abundant constituents of the diet. These compounds bind covalently to families of cysteine-containing, redox-sensing proteins that constitute the electrophile-responsive proteome, the subproteomes of which are found in localized intracellular domains. These include those proteins controlling responses to oxidative stress in the cytosol-notably the Keap1-Nrf2 pathway, the autophagy-lysosomal pathway, and proteins in other compartments including mitochondria and endoplasmic reticulum. The signaling pathways through which electrophiles function have unique characteristics that could be exploited for novel therapeutic interventions; however, development of such therapeutic strategies has been challenging due to a lack of basic understanding of the mechanisms controlling this form of redox signaling. In this review, we discuss current knowledge of the basic mechanisms of thiol-electrophile signaling and its potential impact on the translation of this important field of redox biology to the clinic. Emerging understanding of thiol-electrophile interactions and redox signaling suggests replacement of the oxidative stress hypothesis with a new redox biology paradigm, which provides an exciting and influential framework for guiding translational research.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, and Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY, USA; Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA.
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Kansanen
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Veteran Affairs Medical Center, Birmingham, AL 35294, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Veteran Affairs Medical Center, Birmingham, AL 35294, USA. Electronic address: Darley@uab.edu.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000627:therapeutic use; D001343:Autophagy / Q000235:genetics*; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; C027576:4-hydroxy-2-nonenal
keywords: Bioenergetics; Electrophiles; Keap1; Nrf2