RAB7A GTPase Is Involved in Mitophagosome Formation and Autophagosome-Lysosome Fusion in N2a Cells Treated with the Prion Protein Fragment 106-126
RAB7A GTPase Is Involved in Mitophagosome Formation and Autophagosome-Lysosome Fusion in N2a Cells Treated with the Prion Protein Fragment 106-126
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朊蛋白片段106-126处理N2a细胞RAB7A GTPase参与自噬体形成和自噬体-溶酶体融合
DOI：
10.1007/s12035-022-03118-5
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发表时间：
2022-11-30
影响因子：
5.1
通讯作者：
Yang, Lifeng
中科院分区：
文献类型：
--
作者：
Li, Zhiping;Lai, Mengyu;Yang, Lifeng
线粒体和溶酶体之间的通信失败导致线粒体功能失调，这可能诱发线粒体相关的神经退行性疾病。在这里，我们发现RAB7A， rabb家族的一个小GTPase，介导这两个重要细胞器之间的串扰，以维持PrP106-126处理的N2a细胞的稳态。具体来说，我们证明了PrP106-126引起的N2a细胞的线粒体自噬缺陷与线粒体中RAB7A定位失调有关。缺乏RAB7A的细胞显示线粒体与溶酶体共定位减少，线粒体蛋白表达显著增加，导致线粒体自噬受到抑制。相反，gtp结合的RAB7A过表达直接诱导溶酶体与线粒体共定位。进一步的研究表明，gtp结合的RAB7A通过支持自噬体的生物发生来保护线粒体稳态。此外，我们认为RAB7A的缺失会导致溶酶体的形态学改变，从而阻止自噬体与溶酶体的融合，并干扰溶酶体内自噬货物的分解。过表达gtp结合的RAB7A也能减轻prp106 -126诱导的线粒体形态学损伤和功能障碍，减少神经元凋亡。总的来说，我们的数据表明RAB7A成功地将线粒体驱动到自噬体腔内进行降解，这表明蛋白质毒性应激从线粒体到溶酶体的交流需要RAB7A作为信号分子，在受到干扰的线粒体网络及其重塑之间建立联系。这些发现表明，调节线粒体自噬的小分子有可能调节细胞稳态和神经退行性疾病的临床过程。
Failed communication between mitochondria and lysosomes causes dysfunctional mitochondria, which may induce mitochondria-related neurodegenerative diseases. Here, we show that RAB7A, a small GTPase of the Rab family, mediates the crosstalk between these two important organelles to maintain homeostasis in N2a cells treated with PrP106-126. Specifically, we demonstrate that mitophagy deficiency in N2a cells caused by PrP106-126 is associated with dysregulated RAB7A localization in mitochondria. Cells lacking RAB7A display decreased mitochondrial colocalization with lysosomes and significantly increased mitochondrial protein expression, resulting in inhibited mitophagy. In contrast, overexpression of GTP-bound RAB7A directly induces lysosome colocalization with mitochondria. Further study revealed that GTP-bound RAB7A protects mitochondrial homeostasis by supporting autophagosome biogenesis. Moreover, we suggest that depletion of RAB7A leads to gross morphological changes in lysosomes, which prevents autophagosome-lysosome fusion and interferes with the breakdown of autophagic cargo within lysosomes. Overexpression of GTP-bound RAB7A can also alleviate PrP106-126-induced morphological damage and dysfunction of mitochondria, reducing neuronal apoptosis. Collectively, our data demonstrate that RAB7A successfully drives mitochondria to the autophagosomal lumen for degradation, suggesting that the communication of proteotoxic stress from mitochondria to lysosomes requires RAB7A, as a signaling molecule, to establish a link between the disturbed mitochondrial network and its remodeling. These findings indicate that small molecules regulating mitophagy have the potential to modulate cellular homeostasis and the clinical course of neurodegenerative diseases.