Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
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线粒体HSF 1触发亨廷顿病的线粒体功能障碍和神经变性
DOI：
10.15252/emmm.202215851
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发表时间：
2022-07-07
影响因子：
11.1
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中科院分区：
文献类型：
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作者：
蛋白质在线粒体的异常定位干扰线粒体功能，并导致亨廷顿病（HD）的发病机制。然而，关键因素和分子机制仍然难以捉摸。在这里，我们发现热休克转录因子1（HSF1）在HD细胞模型、YAC 128小鼠模型和源自HD诱导多能干细胞（iPSC）的人类纹状体类器官的线粒体中积累。纹状体中线粒体靶向HSF1（mtHSF1）的过度表达导致小鼠神经退行性变和HD样行为。从机制上讲，mtHSF1通过激活发动蛋白相关蛋白1（Drp1）在S616的磷酸化来促进线粒体分裂。此外，mtHSF1抑制单链DNA结合蛋白1（SSBP 1）寡聚体形成，导致线粒体DNA（mtDNA）缺失。DH1（一种独特的肽抑制剂）对HSF1线粒体定位的抑制消除了HSF1诱导的线粒体异常，并改善了HD动物模型和人类纹状体类器官中的缺陷。总之，我们的研究结果描述了HSF1在线粒体功能障碍中的作用，这可能为HD提供了一个有希望的治疗靶点。抑制线粒体HSF 1（mtHSF 1）可恢复亨廷顿病（HD）小鼠的线粒体功能并减缓神经变性，这表明mtHSF 1可能是治疗HD的治疗靶点。
Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington’s disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria‐targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD‐like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin‐related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single‐stranded DNA‐binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1‐induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD. Inhibition of mitochondrial HSF1(mtHSF1) restores mitochondrial function and slows neurodegeneration in Huntington's Disease (HD) mice, suggesting that mtHSF1 might be a therapeutic target for treating HD.