Targeting cellular respiration as a therapeutic strategy in glioblastoma

Abstract

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.