Abstract
Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.
Highlights
In glioblastoma multiforme (GBM), mTOR is activated and autophagy is inhibited [1].This, in turn, inhibits cell differentiation and fosters proliferation of glioblastoma stem progenitor cells [2]
This dosing and timing reproduce previous published data, when the dose–response of rapamycin to stimulate mitochondrial biogenesis reached a plateau at 10 nM rapamycin [10]
The present research study quantifies some facets of mitochondrial status in baseline condition and following rapamycin within GBM cells
Summary
In glioblastoma multiforme (GBM), mTOR is activated and autophagy is inhibited [1]. This, in turn, inhibits cell differentiation and fosters proliferation of glioblastoma stem progenitor cells [2]. In a very recent study we documented a suppression of mitochondrial biogenesis, which was restored by rapamycin [10]. To encompass the knowledge of mitochondrial status in GBM cells in the present study we document mitochondrial fission, fusion, and mitophagy. Fission and mitophagy are expected to buffer cell damage generated by altered mitochondria [20,21,22]. This study wishes to add evidence on how specific alterations of mitophagy and mitochondrial status may be relevant for GBM malignancy [13,14,16,23,24,25,26,27,28,29,30,31,32,33]
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