title: Nitration of Hsp90 on Tyrosine 33 Regulates Mitochondrial Metabolism.
abstract: Peroxynitrite production and tyrosine nitration are present in several pathological conditions, including neurodegeneration, stroke, aging, and cancer. Nitration of the pro-survival chaperone heat shock protein 90 (Hsp90) in position 33 and 56 induces motor neuron death through a toxic gain-of-function. Here we show that nitrated Hsp90 regulates mitochondrial metabolism independently of the induction of cell death. In PC12 cells, a small fraction of nitrated Hsp90 was located on the mitochondrial outer membrane and down-regulated mitochondrial membrane potential, oxygen consumption, and ATP production. Neither endogenous Hsp90 present in the homogenate nor unmodified and fully active recombinant Hsp90 was able to compete with the nitrated protein for the binding to mitochondria. Moreover, endogenous or recombinant Hsp90 did not prevent the decrease in mitochondrial activity but supported nitrated Hsp90 mitochondrial gain-of-function. Nitrotyrosine in position 33, but not in any of the other four tyrosine residues prone to nitration in Hsp90, was sufficient to down-regulate mitochondrial activity. Thus, in addition to induction of cell death, nitrated Hsp90 can also regulate mitochondrial metabolism, suggesting that depending on the cell type, distinct Hsp90 nitration states regulate different aspects of cellular metabolism. This regulation of mitochondrial homeostasis by nitrated Hsp90 could be of particular relevance in cancer cells.
authors.affiliation: From the Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32827, mariaclara.franco@ucf.edu.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Franco
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Karina C
authors.initials: KC
authors.lastname: Ricart
authors.affiliation: Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, Buenos Aires C1120AAR, Argentina.
authors.forename: Analía S
authors.initials: AS
authors.lastname: Gonzalez
authors.affiliation: From the Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32827.
authors.forename: Cassandra N
authors.initials: CN
authors.lastname: Dennys
authors.affiliation: From the Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32827.
authors.forename: Pascal A
authors.initials: PA
authors.lastname: Nelson
authors.affiliation: ThermoFisher Scientific, Eugene, Oregon 97402, and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Janes
authors.affiliation: Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Mehl
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Aimee
authors.initials: A
authors.lastname: Landar
authors.affiliation: From the Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32827.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estévez
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D004734:Energy Metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D016716:PC12 Cells; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D000255:Adenosine Triphosphate
keywords: energy metabolism; heat shock protein 90 (Hsp90); mitochondria; peroxynitrite; reactive nitrogen species (RNS); redox signaling; tyrosine nitration