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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. Synopsis: 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. HSF1 mislocalizes to mitochondria in various HD models.mtHSF1 induces mitochondrial dysfunction by disrupting their dynamic balance and mtDNA replication.mtHSF1 causes neurodegeneration and HD‐like behavior in mice.HD‐associated neuropathology and behavioral deficits are improved by peptide inhibitor DH1. [ABSTRACT FROM AUTHOR]

Abstract 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.