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Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to Be Modified by PINK1 Absence.

Cells(2020)

Cited 10|Views40
Abstract
Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson's disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.
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synuclein,CPT1A,MMP14,PYGL,Tfrc,Ireb2,Pgrmc1,Hmox1,Cyp46a1,Slc11a2,Slc25a37,iron overload versus deprivation,nucleotide metabolism,neurodegeneration
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要点】:该论文通过系统调查铁稳态机制,发现PINK1缺失会改变铁蛋白超家族和核苷酸监控调节,铁剥夺通过激活线粒体自噬和延长秀丽线虫寿命,而在帕金森病患者中,PINK1-PRKN突变通过缺陷线粒体自噬导致铁积累和寿命缩短,铁螯合药物可能作为帕金森病治疗的潜力。

方法】:通过全局蛋白质组学和靶向转录分析评估铁剥夺对小鼠细胞蛋白质和转录的影响。

实验】:在铁剥夺条件下,小鼠细胞中与铁结合的核苷酸代谢酶(尤其是XDH和铁蛋白同系物RRM2)的蛋白丰度降低,铁代谢相关的核苷酸监控因子的表达也降低,铁过载后PINK1突变对细胞的影响显著,导致核糖体监控因子Abce1和铁蛋白的过度活跃表达,铁蛋白翻译虽然被IRP1抑制。