期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17862-6
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资金
- Wellcome Senior Clinical Research Fellowship [102770/Z/13/Z, 215477/Z/19/Z]
- Lister Institute Research Fellowship
- Wellcome PhD Training Fellowship for Clinicians [205252/Z/16/Z]
- Medical Research Council [MRC_MC_UU_12022/6]
- NIHR Cambridge Biomedical Research Centre
- Evelyn Trust
- Wellcome Strategic Award [100140]
- MRC [MC_UU_12022/6] Funding Source: UKRI
- Wellcome Trust [215477/Z/19/Z, 205252/Z/16/Z] Funding Source: Wellcome Trust
2-oxoglutarate (2-OG or alpha-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.
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