Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2024-10-08 DOI:10.1126/scisignal.adn5805

Omer Abraham, Shifra Ben-Dor, Inna Goliand, Rebecca Haffner-Krausz, Sarah Phoebeluc Colaiuta, Andrew Kovalenko, Avraham Yaron

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引用次数: 0

Abstract

Mitophagy eliminates dysfunctional mitochondria, and defects in this cellular housekeeping mechanism are implicated in various age-related diseases. Here, we found that mitophagy suppression by the protein Siah3 promoted developmental axonal remodeling in mice. Siah3-deficient mice displayed increased peripheral sensory innervation. Cultured Siah3-deficient sensory neurons exhibited delays in both axonal degeneration and caspase-3 activation in response to withdrawal of nerve growth factor. Mechanistically, Siah3 was transcriptionally induced by the loss of trophic support and formed a complex with the cytosolic E3 ubiquitin ligase parkin, a core component of mitophagy, in transfected cells. Axons of Siah3-deficient neurons mounted profound mitophagy upon initiation of degeneration but not under basal conditions. Neurons lacking both Siah3 and parkin did not exhibit the delay in trophic deprivation–induced axonal degeneration or the induction of axonal mitophagy that was seen in Siah3-deficient neurons. Our findings reveal that mitophagy regulation acts as a gatekeeper of a physiological axon elimination program.

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Siah3 是一种生理性有丝分裂抑制因子，可促进轴突变性。

有丝分裂能清除功能失调的线粒体，而这种细胞内务机制的缺陷与多种老年相关疾病有关。在这里，我们发现 Siah3 蛋白抑制有丝分裂可促进小鼠轴突的发育重塑。Siah3缺陷小鼠的外周感觉神经支配增加。培养的Siah3缺陷感觉神经元在神经生长因子撤除后表现出轴突变性和caspase-3激活的延迟。从机理上讲，营养支持的丧失会诱导Siah3转录，并在转染细胞中与细胞质E3泛素连接酶parkin（有丝分裂的核心成分）形成复合物。Siah3 缺陷神经元的轴突在开始变性时会发生严重的有丝分裂，而在基础条件下则不会。同时缺乏Siah3和parkin的神经元并没有表现出营养剥夺诱导的轴突变性延迟或轴突有丝分裂的诱导。我们的研究结果表明，有丝分裂调节是生理轴突消除程序的看门人。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.