Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.
Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.
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DOI：
10.1083/jcb.202006043
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发表时间：
2021-06-07
期刊：
影响因子：
--
通讯作者：
Karbowski M
中科院分区：
文献类型：
--
作者：
Oshima Y;Cartier E;Boyman L;Verhoeven N;Polster BM;Huang W;Kane M;Lederer WJ;Karbowski M
Oshima等人报道，在缺乏Parkin活性的情况下，细胞通过drp1介导的机制适应线粒体蛋白质毒性，包括切断OMM和IMM泛素化，随后自噬机制招募泛素化的IMM蛋白。在这里，我们报道了线粒体翻译保真度（MTF）的急性降低导致线粒体内膜（IMM）蛋白泛素化，包括TRAP1和CPOX，这种泛素化选择性地发生在线粒体外膜（OMM）断裂的线粒体中。泛素化的IMM招募自噬机制。抑制自噬可导致线粒体积累增加，并导致OMM和泛素化IMM的切断。这一过程发生在细胞色素c/CPOX积累的下游，线粒体亚群在整个细胞中分布不均（“马赛克分布”）。马赛克线粒体的形成、OMM切断和IMM泛素化需要活跃的线粒体翻译和线粒体分裂，但不需要促凋亡蛋白Bax和Bak。相反，在帕金森过表达的细胞中，MTF的减少并不导致OMM或IMM泛素化的切断，但它确实诱导了OMM不依赖于drp1的泛素化。此外，高细胞色素c/CPOX线粒体优先被Parkin靶向，这表明在MTF减少的情况下，无论Parkin的表达如何，它们都是线粒体自噬的中间产物。总之，帕金森缺乏症细胞通过drp1介导的机制适应线粒体蛋白质毒性，该机制涉及到OMM的切断和针对泛素化IMM蛋白的自噬。
Oshima et al. report that in the absence of Parkin activity, cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that includes the severing of the OMM and IMM ubiquitination, followed by recruitment of autophagy machinery to the ubiquitinated IMM proteins. Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (“mosaic distribution”). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high–cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.
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DOI：
10.1083/jcb.201401070
发表时间：
2014-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ashrafi G;Schlehe JS;LaVoie MJ;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
13.6
作者：
Boyman L;Karbowski M;Lederer WJ
通讯作者：
Lederer WJ
影响因子：
16
作者：
Heo JM;Livnat-Levanon N;Taylor EB;Jones KT;Dephoure N;Ring J;Xie J;Brodsky JL;Madeo F;Gygi SP;Ashrafi K;Glickman MH;Rutter J
通讯作者：
Rutter J
影响因子：
11.4
作者：
Collins, TJ;Berridge, MJ;Bootman, MD
通讯作者：
Bootman, MD
影响因子：
16
作者：
Cho, Hyo Min;Ryu, Jae Ryun;Sun, Woong
通讯作者：
Sun, Woong