Research Perspectives:

Targeting cellular respiration as a therapeutic strategy in glioblastoma

Enyuan Shang, Trang Thi Thu Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler and Markus D. Siegelin _

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Oncotarget. 2023; 14:419-425. https://doi.org/10.18632/oncotarget.28424

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Enyuan Shang2, Trang Thi Thu Nguyen1, Mike-Andrew Westhoff4, Georg Karpel-Massler3 and Markus D. Siegelin1

1 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA

2 Department of Biological Sciences, Bronx Community College, City University of New York, NY 10453, USA

3 Department of Neurosurgery, Ulm University Medical Center, Ulm 89081, Germany

4 Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm 89081, Germany

Correspondence to:

Markus D. Siegelin, email: [email protected]

Keywords: glioblastoma; metabolism; lactate; carbon tracing; central carbon metabolism

Received: March 15, 2023     Accepted: April 24, 2023     Published: May 04, 2023

Copyright: © 2023 Shang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


While glycolysis is abundant in malignancies, mitochondrial metabolism is significant as well. Mitochondria harbor the enzymes relevant for cellular respiration, which is a critical pathway for both regeneration of reduction equivalents and energy production in the form of ATP. The oxidation of NADH2 and FADH2 are fundamental since NAD and FAD are the key components of the TCA-cycle that is critical to entertain biosynthesis in cancer cells. The TCA-cycle itself is predominantly fueled through carbons from glucose, glutamine, fatty acids and lactate. Targeting mitochondrial energy metabolism appears feasible through several drug compounds that activate the CLPP protein or interfere with NADH-dehydrogenase, pyruvate-dehydrogenase, enzymes of the TCA-cycle and mitochondrial matrix chaperones. While these compounds have demonstrated anti-cancer effects in vivo, recent research suggests which patients most likely benefit from such treatments. Here, we provide a brief overview of the status quo of targeting mitochondrial energy metabolism in glioblastoma and highlight a novel combination therapy.

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