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ABHD11/ROLIP maintains the TCA cycle by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex

ABSTRACT: 2-oxoglutarate (2-OG) relates mitochondrial metabolism to cell function: conversion of 2-OG to succinyl-CoA by the 2-OG dehydrogenase complex (OGDHc) is rate-limiting for the Tricarboxylic Acid (TCA) cycle, but 2-OG is also required for oxygen sensitive enzymes (2-OG dependent dioxygenases) that have diverse biological roles ranging from Hypoxia Inducible Factor (HIF) activation to DNA hydroxymethylation. Here, using the 2-OG-mediated stability of HIFs to screen for genes involved in HIF metabolic activation, we identify ABHD11 (termed regulator of lipoylation, ROLIP) as a mitochondrial hydrolase required for OGDHc function. ROLIP loss decreases OGDHc activity, leading to accumulation of 2-OG and formation of L-2-hydroxyglutarate, which drives HIF activation and decreases DNA hydroxymethylation. Rather than altering constituent components of the OGDHc, ROLIP maintains the cyclical reduction and oxidation of the lipoylated OGDHc by preventing the formation of lipoyl adducts, highlighting ROLIP as a fundamental regulator of lipoylation, the TCA cycle, and 2-OG-dependent signalling.

OTHER RELATED OMICS DATASETS IN: PXD020128

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - alternating - hilic

SUBMITTER: Ana Sofia Henriques da Costa

PROVIDER: MTBLS1875 | MetaboLights | 2020-08-10

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS1875	Other
	FILES	Other
	a_MTBLS1875_LC-MS_alternating_hilic_metabolite_profiling-1.txt	Txt
	a_MTBLS1875_LC-MS_alternating_hilic_metabolite_profiling.txt	Txt
	a_MTBLS1875_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt

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