ABHD11 regulates 2-oxoglutarate abundance by protecting mitochondrial lipoylated proteins from lipid peroxidation damage

• DOI: 10.1101/2020.04.18.048082
• Publication Date: 2020-04-19T11:49:27Z
• Authors: Peter S J Bailey; Brian M Ortmann; Jack W Houghton; Ana S H Costa; Robin Antrobus; Christian Frezza; James A Nathan
• Keywords: 0303 health sciences; 03 medical and health sciences

Abstract 2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases DDs) involved in hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis screen for genetic determinants levels, we uncover a redox lipoylation pathway, on hydrolase ABHD11, signals changes DD function. ABHD11 loss inhibition drives rapid increase levels impairing dehydrogenase complex (OGDHc) – rate limiting step metabolism. Rather than facilitating lipoate conjugation, protects catalytic lipoyl domain from lipid peroxidation products formed oxidative damage, demonstrating requirement repair pathway human cells, highlighting how sensitivity modulates