Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction.
Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction.
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DOI：
10.3390/cells9091922
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发表时间：
2020-08-19
期刊：
影响因子：
6
通讯作者：
Ugalde C
中科院分区：
文献类型：
--
作者：
García-Bartolomé A;Peñas A;Illescas M;Bermejo V;López-Calcerrada S;Pérez-Pérez R;Marín-Buera L;Domínguez-González C;Arenas J;Martín MA;Ugalde C
线粒体氧化磷酸化(OXPHOS)缺陷是能量代谢先天缺陷的主要原因。尽管在遗传基础上取得了相当大的进展，但它们的全球病理生理学后果仍然不确定。以往的研究报道，与复合体III缺乏相关的OXPHOS功能障碍加剧了细胞骨架明胶蛋白(GSN)的表达和线粒体定位，从而促进了细胞的生存反应。在人类中，除了胞浆异构体外，GSN还存在一种分泌到细胞外环境的血浆异构体。我们分析了两种GSN亚型在OXPHOS功能障碍的人类细胞模型和临床模型中的相互作用。无论其病因如何，OXPHOS功能障碍导致线粒体胞质GSN(MGSN)生理性上调，同时血浆GSN(PGSN)水平显著下调。因此，显著高的mGSN/pGSN比率与人类细胞和血液中的OXPHOS缺乏症有关。相比之下，接受过氧化氢或星形孢菌素处理的对照细胞显示，氧化应激或细胞死亡诱导与GSN亚型水平和亚细胞位置的改变没有相关性，这表明它们是OXPHOS功能障碍的特异性。总之，高线粒体与血浆GSN的比率是OXPHOS缺陷的一个有用的细胞指标，有可能用于未来对涉及线粒体的广泛临床疾病的研究。
Mitochondrial oxidative phosphorylation (OXPHOS) defects are the primary cause of inborn errors of energy metabolism. Despite considerable progress on their genetic basis, their global pathophysiological consequences remain undefined. Previous studies reported that OXPHOS dysfunction associated with complex III deficiency exacerbated the expression and mitochondrial location of cytoskeletal gelsolin (GSN) to promote cell survival responses. In humans, besides the cytosolic isoform, GSN presents a plasma isoform secreted to extracellular environments. We analyzed the interplay between both GSN isoforms in human cellular and clinical models of OXPHOS dysfunction. Regardless of its pathogenic origin, OXPHOS dysfunction induced the physiological upregulation of cytosolic GSN in the mitochondria (mGSN), in parallel with a significant downregulation of plasma GSN (pGSN) levels. Consequently, significantly high mGSN-to-pGSN ratios were associated with OXPHOS deficiency both in human cells and blood. In contrast, control cells subjected to hydrogen peroxide or staurosporine treatments showed no correlation between oxidative stress or cell death induction and the altered levels and subcellular location of GSN isoforms, suggesting their specificity for OXPHOS dysfunction. In conclusion, a high mitochondrial-to-plasma GSN ratio represents a useful cellular indicator of OXPHOS defects, with potential use for future research of a wide range of clinical conditions with mitochondrial involvement.
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DOI：
10.1083/jcb.201709172
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kawamata H;Manfredi G
通讯作者：
Manfredi G
影响因子：
29
作者：
Balsa, Eduardo;Marco, Ricardo;Antonio Enriquez, Jose
通讯作者：
Antonio Enriquez, Jose
影响因子：
5.1
作者：
Kulakowska, A.;Drozdowski, W.;Janmey, P. A.
通讯作者：
Janmey, P. A.
影响因子：
4
作者：
Ji, Lina;Chauhan, Abha;Chauhan, Ved
通讯作者：
Chauhan, Ved
影响因子：
4.8
作者：
Bourens, Myriam;Barrientos, Antoni
通讯作者：
Barrientos, Antoni