Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2024 Mar 14;43(8):1545–1569. doi: 10.1038/s44318-024-00065-w

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.

PMC Copyright notice

In normoxia, carbon flux through lower glycolysis matches that of upper glycolysis because LDHA and GOT1-driven MDH1 provide sufficient NAD⁺, which is needed for the flow of carbons (indicated by the high reading of the gauge) to lower glycolysis. The coloured scale for the reading of the gauge indicates flux from upper to lower glycolysis. In early hypoxia, elevation of upper glycolysis increases the requirement for regeneration of NAD⁺, which is supported by an increase in the flux through LDHA and by GOT1-dependent MDH1 activity that does not increase compared to normoxia. However, carbon flow to lower glycolysis is limited by NAD⁺ in early hypoxia, as indicated by the increased efflux of glucose carbons to α-GP. In late hypoxia, increased RC provides additional OAA for MDH1 and, combined with increased LDHA expression, confers additional NAD⁺-regenerating capacity enabling increased flow of carbons to lower glycolysis. In parallel, GOT1 consumes αKG (an essential co-factor for PHDs), which, in combination with lower oxygen, suppresses HIF1α hydroxylation and therefore promotes its stabilisation, leading to robust HIF1α target gene expression later in hypoxia. RC reductive carboxylation.