Residual Complex I Activity Supports Glutamate Catabolism and mtSLP via Canonical Krebs Cycle Activity During Acute Anoxia Without OXPHOS

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells

“…We found that VM-M3 cells were more sensitive to inhibition of glutamine catabolism upstream of succinyl-CoA synthetase using the alpha-ketoglutarate dehydrogenase inhibitor sodium arsenite than from inhibition of complex IV using potassium cyanide. In addition to maintaining oxygen-independent ATP content for glioma cell viability, ATP production through glutamine-driven mSLP can also reduce ATP hydrolysis from a reversal of the ATP synthase reaction during bioenergetic stress (Chinopoulos et al, 2010; Doczi et al, 2023; Ravasz et al, 2024). Our results suggest that glutamine, which has been considered primarily an anaplerotic respiratory fuel for growth, can also be fermented via mSLP, as an energy mechanism that has been largely unrecognized in cancer, especially in gliomas (Wise and Thompson, 2010; Martins et al, 2020; Garcia et al, 2021; Khadka et al, 2021; Ravasz et al, 2024).…”

“…Our 13 C labeling and DON inhibition experiments showed that the extracellular succinate produced in the VM-M3 cells was derived from the glutamine added to the culture media, thus supporting the origin of succinate through the glutaminolysis pathway in these cells. Additionally, succinate can be derived from malate due to complex II reversal in hypoxia (Ravasz et al, 2024). Succinate, like lactate, accumulates extracellularly following acute inhibition of OxPhos under conditions of prolonged diving (Hochachka et al, 1975), ischemia (Taegtmeyer, 1978; Zhang et al, 2018; Chinopoulos, 2019), hemorrhagic shock (Taghavi et al, 2022), and high-intensity muscle exercise (Reddy et al, 2020).…”