Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure

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 and Tríona Ní Chonghaile ()
Additional contact information
Andrew Roe: Royal College of Surgeons in Ireland
Catríona M. Dowling: Royal College of Surgeons in Ireland
Cian D’Arcy: Royal College of Surgeons in Ireland
Daniel Alencar Rodrigues: Royal College of Surgeons in Ireland
Yu Wang: Royal College of Surgeons in Ireland
Matthew Hiller: Royal College of Surgeons in Ireland
Carl Keogh: Royal College of Surgeons in Ireland
Kate E. R. Hollinshead: New York University Langone Medical Center
Massimiliano Garre: Royal College of Surgeons in Ireland
Brenton Cavanagh: Royal College of Surgeons in Ireland
Kieran Wynne: Belfield
Tianyan Liu: Peking University
Zhixing Chen: Peking University
Emma Kerr: Queen’s University
Marie McIlroy: Royal College of Surgeons in Ireland
Jochen H. M. Prehn: Royal College of Surgeons in Ireland
Ingmar Schoen: Royal College of Surgeons in Ireland
Tríona Ní Chonghaile: Royal College of Surgeons in Ireland

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61897-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61897-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61897-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().