{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:01:25Z","timestamp":1783576885034,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,17]],"date-time":"2024-11-17T00:00:00Z","timestamp":1731801600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG 2175\/1\u20101"],"award-info":[{"award-number":["DFG 2175\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FuGGProject\u2010ID403765277"],"award-info":[{"award-number":["FuGGProject\u2010ID403765277"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose.<\/jats:p><jats:p>We employed genetic approaches (stable\/inducible overexpression, CRISPR\/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP\u2010activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC\u20101\u03b1 with the local metabolic and genetic architecture in human glioblastoma tissue sections.<\/jats:p><jats:p>A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC\u20101\u03b1\u2010dependent adaptive programs promoting mitochondrial metabolism. This sensor\u2010effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC\u20101\u03b1 necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC\u20101\u03b1\u2010expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment.<\/jats:p><jats:p>Our findings reveal a cell\u2010intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC\u20101\u03b1 to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC\u20101\u03b1 especially in nonhypoxic tumour regions. Thus, the AMPK\u2010PGC\u20101\u03b1 axis is a candidate for therapeutic inhibition in glioblastoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Points\/Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>AMPK activation induces PGC\u20101\u03b1 expression in glioblastoma during nutrient scarcity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PGC\u20101\u03b1 enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PGC\u20101\u03b1 expression is inversely correlated with hypoxic tumour regions in human glioblastomas.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70030","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T05:48:58Z","timestamp":1731908938000},"source":"Crossref","is-referenced-by-count":7,"title":["An AMP\u2010activated protein kinase\u2010PGC\u20101\u03b1 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