miR-193a-3p increases glycolysis under hypoxia by facilitating Akt phosphorylation and PFKFB3 activation in human macrophages
- Human macrophages infiltrating hypoxic regions alter their metabolism, because oxygen becomes limited. Increased glycolysis is one of the most common cellular adaptations to hypoxia and mostly is regulated via hypoxia-inducible factor (HIF) and RAC-alpha serine/threonine–protein kinase (Akt) signaling, which gets activated under reduced oxygen content. We noticed that micro RNA (miR)-193a-3p enhances Akt phosphorylation at threonine 308 under hypoxia. In detail, miR-193a-3p suppresses the protein abundance of phosphatase PTC7 homolog (PPTC7), which in turn increases Akt phosphorylation. Lowering PPTC7 expression by siRNA or overexpressing miR-193a-3p increases Akt phosphorylation. Vice versa, inhibition of miR-193a-3p attenuates Akt activation and prevents a subsequent increase of glycolysis under hypoxia. Excluding effects of miR-193a-3p and Akt on HIF expression, stabilization, and function, we noticed phosphorylation of 6 phosphofructo-2-kinase/fructose 2,6-bisphosphatase PFKFB3 in response to the PI3K/Akt/mTOR signaling cascade. Inhibition of PFKFB3 blocked an increased glycolytic flux under hypoxia. Apparently, miR-193a-3p balances Akt phosphorylation and dephosphorylation by affecting PPTC7 protein amount. Suppression of PPTC7 increases Akt activation and phosphorylation of PFKFB3, which culminates in higher rates of glycolysis under hypoxia.
Author: | Dominik Christian FuhrmannORCiDGND, Bernhard BrüneORCiD |
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URN: | urn:nbn:de:hebis:30:3-695608 |
DOI: | https://doi.org/10.1007/s00018-022-04146-z |
ISSN: | 1420-9071 |
Parent Title (English): | Cellular and molecular life sciences |
Publisher: | Springer International Publishing AG |
Place of publication: | Cham (ZG) |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2022/01/24 |
Date of first Publication: | 2022/01/24 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2023/08/11 |
Tag: | HIF; PDPK1; PPTC7; mTOR |
Volume: | 79 |
Issue: | 2, art. 89 |
Article Number: | 89 |
Page Number: | 15 |
First Page: | 1 |
Last Page: | 15 |
Note: | Open Access funding enabled and organized by Projekt DEAL. Deutsche Forschungsgemeinschaft BR 999/25-1. |
Institutes: | Medizin |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |