Cell, 2019-05, Vol.177 (6), p.1507-1521.e16
2019
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Details
- Autor(en) / Beteiligte
- Titel
- Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis
- Ist Teil von
- Cell, 2019-05, Vol.177 (6), p.1507-1521.e16
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •FXN null yeast, human cells, and nematodes are fully viable in ambient 1% O2•Hypoxia restores steady-state levels of Fe-S clusters in FXN null cells•Hypoxia acts by directly activating Fe-S synthesis and increasing bioavailable iron•In a murine model of FXN deficiency, ambient oxygen affects the progression of ataxia Hypoxia promotes survival of in vivo models of Friederich’s ataxia by restoring the necessary signaling pathways for Fe-S metabolism associated with mitochondrial function.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2019.03.045Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6911770
- Format
- –
- Schlagworte
- Activating Transcription Factor 4 - metabolism, Animals, Caenorhabditis elegans - metabolism, Female, Frataxin, Friedreich Ataxia - metabolism, HEK293 Cells, Humans, Hypoxia - metabolism, Hypoxia - physiopathology, Iron - metabolism, Iron Regulatory Protein 2 - metabolism, Iron-Binding Proteins - metabolism, Iron-Binding Proteins - physiology, Iron-Sulfur Proteins - metabolism, Iron-Sulfur Proteins - physiology, K562 Cells, Male, Mice, Mice, Knockout, Mitochondria - metabolism, Mitochondrial Proteins - metabolism, NF-E2-Related Factor 2 - metabolism, Oxidative Stress, Saccharomyces cerevisiae - metabolism, Sulfur - metabolism