缺氧通过恢复铁硫簇生物发生来挽救铁载体蛋白缺乏。
Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis.
机构信息
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.
Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
出版信息
Cell. 2019 May 30;177(6):1507-1521.e16. doi: 10.1016/j.cell.2019.03.045. Epub 2019 Apr 25.
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, 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 attenuates the progression of ataxia, whereas breathing 55% O hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.
弗里德赖希共济失调（FRDA）是一种由线粒体蛋白 frataxin（FXN）的隐性突变引起的破坏性多系统疾病。FXN 参与 Fe-S 簇的生物合成，被认为对生存至关重要。在这里，我们报告说，在 1%的环境 O 中生长时，FXN 缺失的酵母、人类细胞和线虫都是完全存活的。在人类细胞中，缺氧恢复了 Fe-S 簇的稳态水平，并使与 FRDA 相关的 ATF4、NRF2 和 IRP2 信号事件正常化。细胞研究和体外重建表明，缺氧通过增加生物可利用铁以及直接激活 Fe-S 合成的 HIF 非依赖性机制起作用。在 FRDA 的小鼠模型中，呼吸 11%的 O 可减轻共济失调的进展，而呼吸 55%的 O 则会加速其进展。我们的工作确定了氧气作为与 FXN 耗竭相关的发病机制中的一个关键环境变量，具有重要的机制和治疗意义。
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