Stoichiometric expression of mtHsp40 and mtHsp70 modulates mitochondrial morphology and cristae structure via Opa1L cleavage.
Stoichiometric expression of mtHsp40 and mtHsp70 modulates mitochondrial morphology and cristae structure via Opa1L cleavage.
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DOI：
10.1091/mbc.e14-02-0762
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发表时间：
2015-06-15
影响因子：
3.3
通讯作者：
Kim SW
中科院分区：
文献类型：
--
作者：
Lee B;Ahn Y;Kang SM;Park Y;Jeon YJ;Rho JM;Kim SW
mtHsp 40和mtHsp 70之间的不平衡增强Opa 1 L切割，导致嵴重塑和最终的线粒体片段化和缺陷OXPHOS。这对于在分子和细胞水平上理解mtHsp 40/mtHsp 70的分子伴侣活性与线粒体生物学之间的功能联系是重要的。线粒体热休克蛋白40（mtHsp 40）的失调和mtHsp 70的功能障碍与线粒体碎片化有关，提示mtHsp 40和mtHsp 70可能在调节线粒体形态中起作用。然而，mtHsp 40失调和mtHsp 70功能障碍引起的线粒体碎片化的机制尚不清楚。此外，线粒体形态学变化的mtHsp 40/mtHsp 70和线粒体功能失调之间的功能联系尚未探讨。我们的免疫共沉淀和蛋白聚集分析表明，过度表达和耗尽的mtHsp 40积累聚集的蛋白在破碎的线粒体。此外，mtHsp 70的损失和缺乏客户端结合域的mtHsp 70突变体的表达引起线粒体片段化。总之，这些数据表明，mtHsp 40与mtHsp 70的分子比例对于它们的伴侣蛋白功能和线粒体形态是重要的。而线粒体易位的Drp 1没有改变，视神经萎缩1（Opa 1）短亚型积累在破碎的线粒体，这表明在这项研究中的线粒体碎片的结果从畸变的线粒体内膜融合。最后，我们发现破碎的线粒体在嵴发育、OXPHOS和ATP产生方面有缺陷。两者合计，我们的数据表明，受损的mtHsp 40和mtHsp 70之间的化学计量促进Opa 1 L裂解，导致嵴开放，减少OXPHOS，并触发线粒体碎片后，减少其伴侣功能。
Imbalance between mtHsp40 and mtHsp70 enhances Opa1L cleavage, leading to cristae remodeling and eventual mitochondrial fragmentation and defective OXPHOS. This is important for understanding functional links between chaperone activity of mtHsp40/mtHsp70 and mitochondrial biology at the molecular and cellular levels. Deregulation of mitochondrial heat-shock protein 40 (mtHsp40) and dysfunction of mtHsp70 are associated with mitochondrial fragmentation, suggesting that mtHsp40 and mtHsp70 may play roles in modulating mitochondrial morphology. However, the mechanism of mitochondrial fragmentation induced by mtHsp40 deregulation and mtHsp70 dysfunction remains unclear. In addition, the functional link between mitochondrial morphology change upon deregulated mtHsp40/mtHsp70 and mitochondrial function has been unexplored. Our coimmunoprecipitation and protein aggregation analysis showed that both overexpression and depletion of mtHsp40 accumulated aggregated proteins in fragmented mitochondria. Moreover, mtHsp70 loss and expression of a mtHsp70 mutant lacking the client-binding domain caused mitochondrial fragmentation. Together the data suggest that the molecular ratio of mtHsp40 to mtHsp70 is important for their chaperone function and mitochondrial morphology. Whereas mitochondrial translocation of Drp1 was not altered, optic atrophy 1 (Opa1) short isoform accumulated in fragmented mitochondria, suggesting that mitochondrial fragmentation in this study results from aberration of mitochondrial inner membrane fusion. Finally, we found that fragmented mitochondria were defective in cristae development, OXPHOS, and ATP production. Taken together, our data suggest that impaired stoichiometry between mtHsp40 and mtHsp70 promotes Opa1L cleavage, leading to cristae opening, decreased OXPHOS, and triggering of mitochondrial fragmentation after reduction in their chaperone function.