Sensory neuropathy-causing mutations in ATL3 affect ER-mitochondria contact sites and impair axonal mitochondrial distribution.
Sensory neuropathy-causing mutations in ATL3 affect ER-mitochondria contact sites and impair axonal mitochondrial distribution.
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DOI：
10.1093/hmg/ddy352
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发表时间：
2019-02-15
影响因子：
3.5
通讯作者：
Janssens S
中科院分区：
文献类型：
--
作者：
Krols M;Asselbergh B;De Rycke R;De Winter V;Seyer A;Müller FJ;Kurth I;Bultynck G;Timmerman V;Janssens S
轴突病是由轴突变性引起的神经退行性疾病，主要影响最长的神经元。其中一些轴突病是由参与内质网 (ER) 成形和动态的蛋白质的遗传缺陷引起的。然而，目前尚不清楚这些缺陷如何影响神经元的存活。鉴于其在细胞内的中心和广泛的地位，内质网是细胞器间通讯的关键参与者。在这里，我们证明了在患有遗传性感觉和自主神经病的患者中发现的 ER 融合蛋白 ATL3 的缺陷，导致 HeLa 细胞和患者来源的成纤维细胞中 ER 与线粒体接触位点的数量增加。这种接触的增加反映在更高的磷脂代谢、上调的自噬和增强的两个细胞器之间的 Ca2+ 串扰上。此外，这些细胞中的线粒体显示出运动性降低，并且表达 ATL3 致病突变的神经元中轴突线粒体的数量大幅减少。这些结果强调了亚细胞细胞器在健康和疾病中的功能相互依赖性，并表明内质网塑造缺陷引起的疾病比之前假设的更为复杂。
Axonopathies are neurodegenerative disorders caused by axonal degeneration, affecting predominantly the longest neurons. Several of these axonopathies are caused by genetic defects in proteins involved in the shaping and dynamics of the endoplasmic reticulum (ER); however, it is unclear how these defects impinge on neuronal survival. Given its central and widespread position within a cell, the ER is a pivotal player in inter-organelle communication. Here, we demonstrate that defects in the ER fusion protein ATL3, which were identified in patients suffering from hereditary sensory and autonomic neuropathy, result in an increased number of ER–mitochondria contact sites both in HeLa cells and in patient-derived fibroblasts. This increased contact is reflected in higher phospholipid metabolism, upregulated autophagy and augmented Ca2+ crosstalk between both organelles. Moreover, the mitochondria in these cells display lowered motility, and the number of axonal mitochondria in neurons expressing disease-causing mutations in ATL3 is strongly decreased. These results underscore the functional interdependence of subcellular organelles in health and disease and show that disorders caused by ER-shaping defects are more complex than previously assumed.
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影响因子：
3.5
作者：
De Vos KJ;Mórotz GM;Stoica R;Tudor EL;Lau KF;Ackerley S;Warley A;Shaw CE;Miller CC
通讯作者：
Miller CC
DOI：
10.1083/jcb.200911024
发表时间：
2010-08-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Friedman JR;Webster BM;Mastronarde DN;Verhey KJ;Voeltz GK
通讯作者：
Voeltz GK
DOI：
10.1083/jcb.200601067
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Glater EE;Megeath LJ;Stowers RS;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
11.4
作者：
Csordás, G;Thomas, AP;Hajnóczky, G
通讯作者：
Hajnóczky, G
DOI：
10.1073/pnas.1606786113
发表时间：
2016-10-04
影响因子：
11.1
作者：
Naon, Deborah;Zaninello, Marta;Scorrano, Luca
通讯作者：
Scorrano, Luca