The role of mitochondrial metabolic efficiency and activity in proliferation of glioblastoma multiforme cells
File(s)
Author(s)
Bae, Haesoo
Type
Thesis
Abstract
Glioblastoma multiforme (GBM, grade IV astrocytoma) is one of the deadliest primary brain tumours, and the energetic requirements for GBM malignancy rely highly upon mitochondrial activity. This study hypothesised that the proliferation of GBM depends on mitochondrial metabolic efficiency and activity, and is likely modulated by Bcl-xL, the anti-apoptotic member of the Bcl-2 family. We demonstrated a significant inducible effect of GBM mitochondria on cancer cell growth when transferred. Immunohistochemistry on human post- mortem tissue discovered the greater expression of mitochondrial Bcl-xL in GBM (compared to control cells or lower-grade glioma cells) without change in the mitochondrial biomass and Bcl-xL binding protein ATPase β. Pharmacological and genetic inhibition of Bcl-xL in primary GBM cells resulted in reduced mitochondrial membrane potential and halted their proliferation. These effects were further characterised by mitochondrial patch clamp electrophysiology in the patient mitochondria sample. Compared with grade 2 astrocytoma mitochondria, mitochondria isolated from GBM tissue showed decreased conductance of the mitochondrial ion leak currents. Direct application of a pharmacological inhibitor of Bcl-xL increased the leak conductance, suggesting Bcl-xL closure of mitochondrial ion leak channels as the modulator of metabolic efficiency. Our single-cell oxygen flux recordings confirmed these results, demonstrating an increase in oxygen consumption of GBM cells upon inhibition of Bcl-xL. Overall, our studies demonstrate a novel role for Bcl-xL in the modulation of metabolic efficiency and proliferation of GBM cells. These findings suggest Bcl-xL modulation of an ion leak conductance in the mitochondria as a therapeutic target for treating GBM.
Version
Open Access
Date Issued
2022-11
Date Awarded
2023-11
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Alavian, Kambiz
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)