Matches in SemOpenAlex for { <https://semopenalex.org/work/W2989134477> ?p ?o ?g. }
Showing items 1 to 71 of
71
with 100 items per page.
- W2989134477 abstract "Introduction Inflamed tissues or solid tumours provide challenging microenvironments for cell survival, whereby localised hypoxia and nutrient scarcity can alter immune responses or drive tumour growth. Cells endure this oxygen deprivation by the induction of Hypoxia Inducible transcription Factors (HIFs), which drive an adaptive gene response to promote survival. Drugs targeting the HIF pathway are being trialled for chronic anaemia, modifying immune responses and preventing tumour growth, highlighting HIFs’ relevance to respiratory disease. However, HIFs not only respond to oxygen abundance, but can also be activated by metabolic changes in response to nutrient availability. Central to understanding metabolic activation of HIFs is the recognition that the oxygen sensors within the HIF pathway, the prolyl hydroxylases (PHDs), also require the Krebs cycle metabolite and essential nutrient 2-oxoglutarate (2-OG/a-ketoglutarate) as substrate for their catalytic activity. Therefore, understanding how cells control 2-OG levels is important. Key determinants of 2-OG metabolism are (1) the 2-oxoglutarate dehydrogenase complex (OGDHc), a rate limiting enzyme within the Krebs cycle, and (2) modification of the OGDHc by lipoylation, a fatty acid cofactor required for enzymatic function. Genetic disruption of the OGDHc or its lipoylation leads to HIF stabilisation, and patients with hereditary mutations in the OGDHc develop tumour syndromes, typical of HIF activation. However, how the OGDHc is regulated is not well understood. Methods and results Using unbiased genetic screens in human cells to find genes involved in HIF metabolic activation, we identify ABHD11 (we term Regulator of Lipoylation (ROLIP)), as an uncharacterised mitochondrial protein that, on depletion, leads to metabolic stabilisation of HIFs. Using cell biology, metabolomics and in vitro enzymatic assays, we show that ROLIP is required for Krebs cycle function and ODGHc activity. ROLIP associates with the OGDHc, but ROLIP depletion does not alter total levels of the enzyme. Instead, ROLIP preserves OGDHc function by protecting the enzyme from oxidative damage and maintaining lipoylation. Summary and importance These studies identify ROLIP as a novel enzyme required for maintaining oxidative phosphorylation, and highlight a new oxygen and metabolic sensing mechanism for controlling HIFs that may be therapeutically tractable." @default.
- W2989134477 created "2019-11-22" @default.
- W2989134477 creator A5005689323 @default.
- W2989134477 creator A5010879514 @default.
- W2989134477 creator A5013887971 @default.
- W2989134477 creator A5027474968 @default.
- W2989134477 creator A5062307085 @default.
- W2989134477 date "2019-11-12" @default.
- W2989134477 modified "2023-09-27" @default.
- W2989134477 title "T6 Identification of ROLIP as a mitochondrial regulator of metabolism and the hypoxia response pathway" @default.
- W2989134477 doi "https://doi.org/10.1136/thorax-2019-btsabstracts2019.6" @default.
- W2989134477 hasPublicationYear "2019" @default.
- W2989134477 type Work @default.
- W2989134477 sameAs 2989134477 @default.
- W2989134477 citedByCount "1" @default.
- W2989134477 countsByYear W29891344772020 @default.
- W2989134477 crossrefType "proceedings-article" @default.
- W2989134477 hasAuthorship W2989134477A5005689323 @default.
- W2989134477 hasAuthorship W2989134477A5010879514 @default.
- W2989134477 hasAuthorship W2989134477A5013887971 @default.
- W2989134477 hasAuthorship W2989134477A5027474968 @default.
- W2989134477 hasAuthorship W2989134477A5062307085 @default.
- W2989134477 hasConcept C104317684 @default.
- W2989134477 hasConcept C160450060 @default.
- W2989134477 hasConcept C165135838 @default.
- W2989134477 hasConcept C178790620 @default.
- W2989134477 hasConcept C185592680 @default.
- W2989134477 hasConcept C192989942 @default.
- W2989134477 hasConcept C203014093 @default.
- W2989134477 hasConcept C540031477 @default.
- W2989134477 hasConcept C55493867 @default.
- W2989134477 hasConcept C62231903 @default.
- W2989134477 hasConcept C6929976 @default.
- W2989134477 hasConcept C7836513 @default.
- W2989134477 hasConcept C86339819 @default.
- W2989134477 hasConcept C86803240 @default.
- W2989134477 hasConcept C8891405 @default.
- W2989134477 hasConcept C95444343 @default.
- W2989134477 hasConceptScore W2989134477C104317684 @default.
- W2989134477 hasConceptScore W2989134477C160450060 @default.
- W2989134477 hasConceptScore W2989134477C165135838 @default.
- W2989134477 hasConceptScore W2989134477C178790620 @default.
- W2989134477 hasConceptScore W2989134477C185592680 @default.
- W2989134477 hasConceptScore W2989134477C192989942 @default.
- W2989134477 hasConceptScore W2989134477C203014093 @default.
- W2989134477 hasConceptScore W2989134477C540031477 @default.
- W2989134477 hasConceptScore W2989134477C55493867 @default.
- W2989134477 hasConceptScore W2989134477C62231903 @default.
- W2989134477 hasConceptScore W2989134477C6929976 @default.
- W2989134477 hasConceptScore W2989134477C7836513 @default.
- W2989134477 hasConceptScore W2989134477C86339819 @default.
- W2989134477 hasConceptScore W2989134477C86803240 @default.
- W2989134477 hasConceptScore W2989134477C8891405 @default.
- W2989134477 hasConceptScore W2989134477C95444343 @default.
- W2989134477 hasLocation W29891344771 @default.
- W2989134477 hasOpenAccess W2989134477 @default.
- W2989134477 hasPrimaryLocation W29891344771 @default.
- W2989134477 hasRelatedWork W10891023 @default.
- W2989134477 hasRelatedWork W19170559 @default.
- W2989134477 hasRelatedWork W21956318 @default.
- W2989134477 hasRelatedWork W27551737 @default.
- W2989134477 hasRelatedWork W32861963 @default.
- W2989134477 hasRelatedWork W35862036 @default.
- W2989134477 hasRelatedWork W36537840 @default.
- W2989134477 hasRelatedWork W36939611 @default.
- W2989134477 hasRelatedWork W5512248 @default.
- W2989134477 hasRelatedWork W19940598 @default.
- W2989134477 isParatext "false" @default.
- W2989134477 isRetracted "false" @default.
- W2989134477 magId "2989134477" @default.
- W2989134477 workType "article" @default.