Department of Biomolecular Sciences and Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot 761000, Israel.
Bioinformatics Unit, Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 761000, Israel.
Sci Signal. 2024 Oct 8;17(857):eadn5805. doi: 10.1126/scisignal.adn5805.
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.
自噬消除功能失调的线粒体，而这种细胞内清理机制的缺陷与各种与年龄相关的疾病有关。在这里，我们发现蛋白 Siah3 的自噬抑制促进了小鼠的发育性轴突重塑。Siah3 缺陷型小鼠表现出外周感觉神经支配的增加。培养的 Siah3 缺陷型感觉神经元在神经生长因子撤出时表现出轴突退化和半胱天冬酶-3 激活的延迟。在机制上，Siah3 是由营养支持的丧失转录诱导的，并与细胞质 E3 泛素连接酶 parkin 形成复合物，后者是自噬的核心成分，在转染细胞中也是如此。在开始退化时，Siah3 缺陷型神经元的轴突会发生深刻的自噬，但在基础条件下则不会。缺乏 Siah3 和 parkin 的神经元在营养剥夺诱导的轴突退化或 Siah3 缺陷型神经元中观察到的轴突自噬诱导方面没有表现出延迟。我们的发现揭示了自噬调节作为生理轴突消除程序的门控作用。
