ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

Peter S. J. Bailey, Brian M. Ortmann, Anthony W. Martinelli, Jack W. Houghton, Ana S. H. Costa, Stephen P. Burr, Robin Antrobus, Christian Frezza and James A. Nathan ()
Additional contact information
Peter S. J. Bailey: University of Cambridge
Brian M. Ortmann: University of Cambridge
Anthony W. Martinelli: Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge
Jack W. Houghton: University of Cambridge
Ana S. H. Costa: MRC Cancer Unit, University of Cambridge
Stephen P. Burr: University of Cambridge
Robin Antrobus: University of Cambridge
Christian Frezza: MRC Cancer Unit, University of Cambridge
James A. Nathan: University of Cambridge

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function. ABHD11 loss or inhibition drives a rapid increase in 2-OG levels by impairing lipoylation of the 2-OG dehydrogenase complex (OGDHc)—the rate limiting step for mitochondrial 2-OG metabolism. Rather than facilitating lipoate conjugation, ABHD11 associates with the OGDHc and maintains catalytic activity of lipoyl domain by preventing the formation of lipoyl adducts, highlighting ABHD11 as a regulator of functional lipoylation and 2-OG metabolism.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-17862-6 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:11:y:2020:i:1:d:10.1038_s41467-020-17862-6

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

DOI: 10.1038/s41467-020-17862-6

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 ().