Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease
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) accumula...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2022-06-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202215851 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761536737804288 |
|---|---|
| author | Chunyue Liu Zixing Fu Shanshan Wu Xiaosong Wang Shengrong Zhang Chu Chu Yuan Hong Wenbo Wu Shengqi Chen Yueqing Jiang Yang Wu Yongbo Song Yan Liu Xing Guo |
| author_facet | Chunyue Liu Zixing Fu Shanshan Wu Xiaosong Wang Shengrong Zhang Chu Chu Yuan Hong Wenbo Wu Shengqi Chen Yueqing Jiang Yang Wu Yongbo Song Yan Liu Xing Guo |
| author_sort | Chunyue Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5ccc4c519e7e441a9304214eb407cf67 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-5ccc4c519e7e441a9304214eb407cf672025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-06-0114711910.15252/emmm.202215851Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's diseaseChunyue Liu0Zixing Fu1Shanshan Wu2Xiaosong Wang3Shengrong Zhang4Chu Chu5Yuan Hong6Wenbo Wu7Shengqi Chen8Yueqing Jiang9Yang Wu10Yongbo Song11Yan Liu12Xing Guo13State Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Interdisciplinary InnoCenter for Organoids, Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Interdisciplinary InnoCenter for Organoids, Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Interdisciplinary InnoCenter for Organoids, Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityState Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Center for Magnetic Resonance, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of SciencesDepartment of Pharmacology, Shenyang Pharmaceutical UniversityState Key Laboratory of Reproductive Medicine, Interdisciplinary InnoCenter for Organoids, Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical UniversityState Key Laboratory of Reproductive Medicine, Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Neurobiology, Interdisciplinary InnoCenter for Organoids, School of Basic Medical Sciences, Nanjing Medical UniversityAbstract 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.https://doi.org/10.15252/emmm.202215851heat shock transcription factor 1human striatal organoidsHuntington's diseasemitochondrial DNAsingle‐stranded DNA‐binding protein 1 |
| spellingShingle | Chunyue Liu Zixing Fu Shanshan Wu Xiaosong Wang Shengrong Zhang Chu Chu Yuan Hong Wenbo Wu Shengqi Chen Yueqing Jiang Yang Wu Yongbo Song Yan Liu Xing Guo Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease EMBO Molecular Medicine heat shock transcription factor 1 human striatal organoids Huntington's disease mitochondrial DNA single‐stranded DNA‐binding protein 1 |
| title | Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease |
| title_full | Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease |
| title_fullStr | Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease |
| title_full_unstemmed | Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease |
| title_short | Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease |
| title_sort | mitochondrial hsf1 triggers mitochondrial dysfunction and neurodegeneration in huntington s disease |
| topic | heat shock transcription factor 1 human striatal organoids Huntington's disease mitochondrial DNA single‐stranded DNA‐binding protein 1 |
| url | https://doi.org/10.15252/emmm.202215851 |
| work_keys_str_mv | AT chunyueliu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT zixingfu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT shanshanwu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT xiaosongwang mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT shengrongzhang mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT chuchu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT yuanhong mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT wenbowu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT shengqichen mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT yueqingjiang mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT yangwu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT yongbosong mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT yanliu mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease AT xingguo mitochondrialhsf1triggersmitochondrialdysfunctionandneurodegenerationinhuntingtonsdisease |