Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

被引：97

作者：

Ast, Tslil ^{[1
,2
,3
,4
]}

Meisel, Joshua D. ^{[1
,2
,3
,4
]}

Patra, Shachin ^{[5
]}

Wang, Hong ^{[1
,2
,3
,4
]}

Grange, Robert M. H. ^{[6
]}

Kim, Sharon H. ^{[1
,2
,3
,4
]}

Calvo, Sarah E. ^{[1
,2
,3
,4
]}

Orefice, Lauren L. ^{[3
,4
]}

Nagashima, Fumiaki ^{[6
]}

Ichinose, Fumito ^{[6
]}

Zapol, Warren M. ^{[6
]}

Ruvkun, Gary ^{[3
,4
]}

Barondeau, David P. ^{[5
]}

Mootha, Vamsi K. ^{[1
,2
,3
,4
]}

机构：

[1] Broad Inst, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[4] Harvard Med Sch, Boston, MA 02115 USA

[5] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA

[6] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA

来源：

CELL | 2019年 / 177卷 / 06期

基金：

美国国家卫生研究院;

关键词：

MOUSE CARDIAC MODEL; FRIEDREICHS-ATAXIA; CLINICAL-FEATURES; GENE DISRUPTION; YEAST FRATAXIN; OXYGEN-THERAPY; EARLY HISTORY; DEFICIENCY; EXPRESSION; PROTEINS;

D O I：

10.1016/j.cell.2019.03.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 O-2, 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% O-2 attenuates the progression of ataxia, whereas breathing 55% O-2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.

引用

页码：1507 / +

页数：31

共 91 条

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