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

Nat Commun. 2020 Aug 13;11(1):4046. doi: 10.1038/s41467-020-17862-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Energy Metabolism / genetics
  • Energy Metabolism / physiology
  • HeLa Cells
  • Humans
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Ketoglutarate Dehydrogenase Complex / metabolism*
  • Ketoglutaric Acids / metabolism*
  • Mitochondria / metabolism*
  • Models, Biological
  • Mutagenesis / genetics
  • Mutagenesis / physiology*
  • Serine Proteases / genetics
  • Serine Proteases / metabolism*


  • Ketoglutaric Acids
  • Ketoglutarate Dehydrogenase Complex
  • ABHD11 protein, human
  • Serine Proteases