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bioRxiv · 10.1101/2020.04.18.048082

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

Bailey, P. S.·Ortmann, B. M.·Houghton, J. W.·Costa, A. S. H.·Antrobus, R.·Frezza, C.·Nathan, J. A.
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Abstract

2-oxoglutarate (2-OG or -ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases (2-OG DDs) 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 DD 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 protects the catalytic lipoyl domain from lipid peroxidation products formed by oxidative damage, demonstrating a requirement for a lipoyl repair pathway in human cells, and highlighting how the redox sensitivity of lipoylation modulates 2-OG metabolism.

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Bailey, P. S., Ortmann, B. M., Houghton, J. W., Costa, A. S. H., Antrobus, R., Frezza, C., Nathan, J. A.. 2020-04-18. ABHD11 regulates 2-oxoglutarate abundance by protecting mitochondrial lipoylated proteins from lipid peroxidation damage. https://doi.org/10.1101/2020.04.18.048082

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