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.

中文翻译：

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线粒体 HSF1 引发亨廷顿病中的线粒体功能障碍和神经变性

蛋白质对线粒体的异常定位会扰乱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、YAC128 小鼠模型和源自 HD 诱导的多能干细胞 (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 S616 的动力相关蛋白 1 (Drp1) 磷酸化来促进线粒体裂变。此外，mtHSF1 抑制单链 DNA 结合蛋白 1 (SSBP1) 寡聚体的形成，从而导致线粒体 DNA (mtDNA) 缺失。DH1（一种独特的肽抑制剂）抑制 HSF1 线粒体定位可消除 HSF1 诱导的线粒体异常并改善 HD 动物模型和人类纹状体类器官的缺陷。总之，我们的研究结果描述了 HSF1 在促成线粒体功能障碍中的意想不到的作用，这可能为 HD 提供有希望的治疗靶点。