Reference - Detail
| RRC ID | 59442 |
|---|---|
| Author | Ast T, Meisel JD, Patra S, Wang H, Grange RMH, Kim SH, Calvo SE, Orefice LL, Nagashima F, Ichinose F, Zapol WM, Ruvkun G, Barondeau DP, Mootha VK. |
| Title | Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis. |
| Journal | Cell |
| Abstract |
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. |
| Volume | 177(6) |
| Pages | 1507-1521.e16 |
| Published | 2019-5-30 |
| DOI | 10.1016/j.cell.2019.03.045 |
| PII | S0092-8674(19)30346-0 |
| PMID | 31031004 |
| PMC | PMC6911770 |
| MeSH | 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 |
| IF | 36.216 |
| Times Cited | 18 |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | X(Twitter) |
| Total number of mentions | 60 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm5913 tm4696 tm4941 tm3516 tm3867 tm2983 |