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The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes
S. Loopmans, K. Rohlenova, T. van Brussel, I. Stockmans, K. Moermans, N. Peredo, P. Carmeliet, D. Lambrechts, S. Stegen, G. Carmeliet
Jazyk angličtina Země Německo
Typ dokumentu časopisecké články
- MeSH
- chondrocyty * metabolismus MeSH
- ferroptóza * fyziologie MeSH
- glukosa-6-fosfátdehydrogenasa metabolismus MeSH
- glukosa metabolismus MeSH
- myši MeSH
- oxidace-redukce MeSH
- oxidační stres * MeSH
- pentózofosfátový cyklus * MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- sbalování proteinů * MeSH
- signální dráha UPR MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.
Center for Biotechnology Khalifa University of Science and Technology Abu Dhabi United Arab Emirates
Laboratory of Translational Genetics VIB Center for Cancer Biology Leuven Belgium
VIB Bioimaging Core Leuven Center for Brain and Disease Research Leuven Belgium
VIB Bioimaging Core Leuven Department of Neurosciences KU Leuven Leuven Belgium
Citace poskytuje Crossref.org
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