Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure
Abstract Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negativ...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61897-6 |
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| author | Andrew Roe Catríona M. Dowling Cian D’Arcy Daniel Alencar Rodrigues Yu Wang Matthew Hiller Carl Keogh Kate E. R. Hollinshead Massimiliano Garre Brenton Cavanagh Kieran Wynne Tianyan Liu Zhixing Chen Emma Kerr Marie McIlroy Jochen H. M. Prehn Ingmar Schoen Tríona Ní Chonghaile |
| author_facet | Andrew Roe Catríona M. Dowling Cian D’Arcy Daniel Alencar Rodrigues Yu Wang Matthew Hiller Carl Keogh Kate E. R. Hollinshead Massimiliano Garre Brenton Cavanagh Kieran Wynne Tianyan Liu Zhixing Chen Emma Kerr Marie McIlroy Jochen H. M. Prehn Ingmar Schoen Tríona Ní Chonghaile |
| author_sort | Andrew Roe |
| collection | DOAJ |
| description | Abstract Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism. |
| format | Article |
| id | doaj-art-7d4d3c256d494c52b8a3132c0faf0de4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7d4d3c256d494c52b8a3132c0faf0de42025-08-20T04:03:02ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-61897-6Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structureAndrew Roe0Catríona M. Dowling1Cian D’Arcy2Daniel Alencar Rodrigues3Yu Wang4Matthew Hiller5Carl Keogh6Kate E. R. Hollinshead7Massimiliano Garre8Brenton Cavanagh9Kieran Wynne10Tianyan Liu11Zhixing Chen12Emma Kerr13Marie McIlroy14Jochen H. M. Prehn15Ingmar Schoen16Tríona Ní Chonghaile17Department of Physiology and Medical Physics, Royal College of Surgeons in IrelandDepartment of Medicine, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandDepartment of Radiation Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical CenterSuper Resolution Imaging Consortium (SRIC), Department of Chemistry, Royal College of Surgeons in IrelandCellular & Molecular Imaging Core, Royal College of Surgeons in IrelandSystems Biology Ireland, School of Medicine, University College Dublin, BelfieldCollege of Future Technology, Peking UniversityCollege of Future Technology, Peking UniversityPatrick G Johnson Centre for Cancer Research, Queen’s UniversityDepartment of Surgery, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandSchool of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in IrelandAbstract Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.https://doi.org/10.1038/s41467-025-61897-6 |
| spellingShingle | Andrew Roe Catríona M. Dowling Cian D’Arcy Daniel Alencar Rodrigues Yu Wang Matthew Hiller Carl Keogh Kate E. R. Hollinshead Massimiliano Garre Brenton Cavanagh Kieran Wynne Tianyan Liu Zhixing Chen Emma Kerr Marie McIlroy Jochen H. M. Prehn Ingmar Schoen Tríona Ní Chonghaile Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure Nature Communications |
| title | Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure |
| title_full | Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure |
| title_fullStr | Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure |
| title_full_unstemmed | Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure |
| title_short | Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure |
| title_sort | inhibition of hdac6 alters fumarate hydratase activity and mitochondrial structure |
| url | https://doi.org/10.1038/s41467-025-61897-6 |
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