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Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis.
Ast, Tslil; Meisel, Joshua D; Patra, Shachin; Wang, Hong; Grange, Robert M H; Kim, Sharon H; Calvo, Sarah E; Orefice, Lauren L; Nagashima, Fumiaki; Ichinose, Fumito; Zapol, Warren M; Ruvkun, Gary; Barondeau, David P; Mootha, Vamsi K.
Afiliação
  • Ast T; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Meisel JD; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Patra S; Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Wang H; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Grange RMH; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Kim SH; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Calvo SE; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Orefice LL; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Nagashima F; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Ichinose F; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Zapol WM; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Ruvkun G; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Barondeau DP; Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Mootha VK; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. E
Cell ; 177(6): 1507-1521.e16, 2019 05 30.
Article em En | MEDLINE | ID: mdl-31031004
Friedreich's ataxia (FRDA) is a devastating, multisystemic disorder caused by recessive mutations in the mitochondrial protein frataxin (FXN). FXN participates in the biosynthesis of Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O2, FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in vitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis. In a mouse model of FRDA, breathing 11% O2 attenuates the progression of ataxia, whereas breathing 55% O2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Ligação ao Ferro / Proteínas Ferro-Enxofre / Hipóxia Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Ligação ao Ferro / Proteínas Ferro-Enxofre / Hipóxia Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos