TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria.
TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria.
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DOI：
10.1016/j.celrep.2023.112454
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发表时间：
2023-04
期刊：
影响因子：
8.8
通讯作者：
Shiori Akabane;Kiyona Watanabe;H. Kosako;S. Yamashita;K. Nishino;Masahiro Kato;Shiori Sekine;T. Kanki;N. Matsuda;T. Endo;T. Oka
中科院分区：
文献类型：
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作者：
Shiori Akabane;Kiyona Watanabe;H. Kosako;S. Yamashita;K. Nishino;Masahiro Kato;Shiori Sekine;T. Kanki;N. Matsuda;T. Endo;T. Oka
PINK1被自磷酸化激活并形成高分子量复合物，从而通过自噬启动受损线粒体的选择性清除。除了线粒体外膜复合物的易位酶，含有PINK1的蛋白质复合物的成员仍然不清楚。通过质谱分析PINK1共免疫沉淀物，我们确定内膜蛋白TIM23作为PINK1复合物的一个组成部分。TIM23下调降低PINK1水平并显著延迟自磷酸化，表明TIM23促进PINK1响应去极化的积累。此外，线粒体蛋白酶OMA1的失活不仅增强了PINK1的积累，而且还抑制了由TIM23下调诱导的PINK1水平的降低，这表明TIM23通过保护免受OMA1的降解而促进PINK1的活化。事实上，不能与TIM23相互作用的致病性PINK1突变体的缺陷通过OMA1失活而部分恢复。这些发现表明，TIM23通过保护PINK1在激活线粒体自噬中起着独特的作用。
PINK1 is activated by autophosphorylation and forms a high-molecular-weight complex, thereby initiating the selective removal of damaged mitochondria by autophagy. Other than translocase of the outer mitochondrial membrane complexes, members of PINK1-containing protein complexes remain obscure. By mass spectrometric analysis of PINK1 co-immunoprecipitates, we identify the inner membrane protein TIM23 as a component of the PINK1 complex. TIM23 downregulation decreases PINK1 levels and significantly delays autophosphorylation, indicating that TIM23 promotes PINK1 accumulation in response to depolarization. Moreover, inactivation of the mitochondrial protease OMA1 not only enhances PINK1 accumulation but also represses the reduction in PINK1 levels induced by TIM23 downregulation, suggesting that TIM23 facilitates PINK1 activation by safeguarding against degradation by OMA1. Indeed, deficiencies of pathogenic PINK1 mutants that fail to interact with TIM23 are partially restored by OMA1 inactivation. These findings indicate that TIM23 plays a distinct role in activating mitochondrial autophagy by protecting PINK1.