title: Redox regulation of mitochondrial proteins and proteomes by cysteine thiol switches.
abstract: Mitochondria are hotspots of cellular redox biochemistry. Respiration as a defining mitochondrial function is made up of a series of electron transfers that are ultimately coupled to maintaining the proton motive force, ATP production and cellular energy supply. The individual reaction steps involved require tight control and flexible regulation to maintain energy and redox balance in the cell under fluctuating demands. Redox regulation by thiol switching has been a long-standing candidate mechanism to support rapid adjustment of mitochondrial protein function at the posttranslational level. Here we review recent advances in our understanding of cysteine thiol switches in the mitochondrial proteome with a focus on their operation in vivo. We assess the conceptual basis for thiol switching in mitochondria and discuss to what extent insights gained from in vitro studies may be valid in vivo, considering thermodynamic, kinetic and structural constraints. We compare functional proteomic approaches that have been used to assess mitochondrial protein thiol switches, including thioredoxin trapping, redox difference gel electrophoresis (redoxDIGE), isotope-coded affinity tag (OxICAT) and iodoacetyl tandem mass tag (iodoTMT) labelling strategies. We discuss conditions that may favour active thiol switching in mitochondrial proteomes in vivo, and appraise recent advances in dissecting their impact using combinations of in vivo redox sensing and quantitative redox proteomics. Finally we focus on four central facets of mitochondrial biology, aging, carbon metabolism, energy coupling and electron transport, exemplifying the current emergence of a mechanistic understanding of mitochondrial regulation by thiol switching in living plants and animals.
authors.affiliation: Plant Energy Biology Lab, Institute of Crop Science and Resource Conservation (INRES), University of Bonn, Friedrich-Ebert-Allee 144, 53113 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nietzel
authors.affiliation: Competence Center Functional Genomics, Junior Research Group Pathoproteomics, University of Greifswald, F.-L.-Jahnstrasse 15, 17489 Greifswald, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Mostertz
authors.affiliation: Competence Center Functional Genomics, Junior Research Group Pathoproteomics, University of Greifswald, F.-L.-Jahnstrasse 15, 17489 Greifswald, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Hochgräfe
authors.affiliation: Plant Energy Biology Lab, Institute of Crop Science and Resource Conservation (INRES), University of Bonn, Friedrich-Ebert-Allee 144, 53113 Bonn, Germany. Electronic address: markus.schwarzlander@uni-bonn.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwarzländer
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D019069:Cell Respiration; D003545:Cysteine / Q000378:metabolism*; D004734:Energy Metabolism; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D010944:Plants; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000378:metabolism*; D018892:Proton-Motive Force; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D020543:Proteome; D013438:Sulfhydryl Compounds; D003545:Cysteine
keywords: Complex I; Cysteine; IodoTMT; Mitochondria; OxICAT; Proteomics; Redox regulation; RedoxDIGE; Respiration; TCA cycle; Thiol protein; Thiol switch; Uncoupling protein