Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A.
Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A.
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DOI：
10.1080/15548627.2016.1190072
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发表时间：
2016-09
期刊：
影响因子：
13.3
通讯作者：
Hilfiker S
中科院分区：
文献类型：
--
作者：
Fernández B;Fdez E;Gómez-Suaga P;Gil F;Molina-Villalba I;Ferrer I;Patel S;Churchill GC;Hilfiker S
各种神经退行性疾病与脑铁含量增加有关。已知铁会引起氧化应激，从而促进细胞死亡。尽管已知内溶酶体作为细胞内铁储存细胞器，但铁增加对内溶酶体功能的影响以及调节内溶酶体铁释放对细胞活力的影响在很大程度上仍然未知。在这里，我们表明，增加细胞内铁导致与受损的细胞内蛋白质聚集体的自噬清除，增加胞质氧化应激和增加细胞死亡相关的内溶酶体改变。这些作用受到NAADP的调节，NAADP是一种有效的第二信使，据报道靶向内溶酶体TPCN（2孔通道）。与内溶酶体铁储存一致，细胞溶质铁水平由NAADP调节，并且当过表达活性而非活性TPCN时检测到增加的细胞溶质铁，表明这些通道可以调节内溶酶体铁释放。在NAADP拮抗剂存在下或当抑制RAB7A活性时，由改变的溶酶体内铁处理触发的细胞死亡被废除。两者合计，我们的研究结果表明，增加的内溶酶体铁导致细胞死亡与增加的细胞溶质氧化应激以及自噬损伤，这些影响受到调制的内溶酶体离子通道活性的RAB7A依赖性的方式。这些数据突出了与细胞内铁负荷增加相关的神经退行性疾病的替代治疗策略。
Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load.
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DOI：
10.1074/jbc.m110.162073
发表时间：
2010-12-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Brailoiu E;Rahman T;Churamani D;Prole DL;Brailoiu GC;Hooper R;Taylor CW;Patel S
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DOI：
10.1016/j.bbamcr.2011.05.005
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2011-08-01
影响因子：
5.1
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Rosado, Juan A.
影响因子：
4.8
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DOI：
10.1083/jcb.200904073
发表时间：
2009-07-27
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影响因子：
--
作者：
Brailoiu E;Churamani D;Cai X;Schrlau MG;Brailoiu GC;Gao X;Hooper R;Boulware MJ;Dun NJ;Marchant JS;Patel S
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Patel S
影响因子：
64.5
作者：
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通讯作者：
Ren D