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ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy [Cell Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2025053118
Olivia Harding, Chantell S. Evans, Junqiang Ye, Jonah Cheung, Tom Maniatis, Erika L. F. Holzbaur

TANK-binding kinase 1 (TBK1) is a multifunctional kinase with an essential role in mitophagy, the selective clearance of damaged mitochondria. More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia, including missense mutations that disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. We investigated how ALS-associated mutations in TBK1 affect Parkin-dependent mitophagy using imaging to dissect the molecular mechanisms involved in clearing damaged mitochondria. Some mutations cause severe dysregulation of the pathway, while others induce limited disruption. Mutations that abolish either TBK1 dimerization or kinase activity were insufficient to fully inhibit mitophagy, while mutations that reduced both dimerization and kinase activity were more disruptive. Ultimately, both TBK1 recruitment and OPTN phosphorylation at S177 are necessary for engulfment of damaged mitochondra by autophagosomal membranes. Surprisingly, we find that ULK1 activity contributes to the phosphorylation of OPTN in the presence of either wild-type or kinase-inactive TBK1. In primary neurons, TBK1 mutants induce mitochondrial stress under basal conditions; network stress is exacerbated with further mitochondrial insult. Our study further refines the model for TBK1 function in mitophagy, demonstrating that some ALS-linked mutations likely contribute to disease pathogenesis by inducing mitochondrial stress or inhibiting mitophagic flux. Other TBK1 mutations exhibited much less impact on mitophagy in our assays, suggesting that cell-type–specific effects, cumulative damage, or alternative TBK1-dependent pathways such as innate immunity and inflammation also factor into the development of ALS in affected individuals.



中文翻译:

TBK1 中 ALS 和 FTD 相关的错义突变对线粒体自噬有不同的破坏 [细胞生物学]

TANK 结合激酶 1 (TBK1) 是一种多功能激酶,在线粒体自噬(选择性清除受损线粒体)中起重要作用。TBK1 中有超过 90 个不同的突变与肌萎缩侧索硬化 (ALS) 和额颞叶痴呆有关,包括破坏 TBK1 二聚化、与线粒体自噬受体视神经磷酸酶 (OPTN) 相关联、自动激活或催化磷酸化能力的错义突变。我们使用成像研究了 TBK1 中与 ALS 相关的突变如何影响 Parkin 依赖性线粒体自噬,以剖析清除受损线粒体所涉及的分子机制。一些突变导致该途径的严重失调,而另一些突变则导致有限的破坏。消除 TBK1 二聚化或激酶活性的突变不足以完全抑制线粒体自噬,而同时降低二聚化和激酶活性的突变更具破坏性。最终,S177 的 TBK1 募集和 OPTN 磷酸化对于自噬体膜吞噬受损线粒体是必要的。令人惊讶的是,我们发现在野生型或激酶失活的 TBK1 存在下,ULK1 活性有助于 OPTN 的磷酸化。在初级神经元中,TBK1 突变体在基础条件下诱导线粒体应激;进一步的线粒体损伤加剧了网络压力。我们的研究进一步完善了线粒体自噬中 TBK1 功能的模型,表明一些与 ALS 相关的突变可能通过诱导线粒体应激或抑制线粒体自噬通量来促进疾病的发病机制。在我们的分析中,其他 TBK1 突变对线粒体自噬的影响要小得多,

更新日期:2021-06-08
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