DRP1-mediated mitochondrial dynamics orchestrate EMT in glioblastoma cells

Abstract

BackgroundEpithelial to mesenchymal transition (EMT), a differentiation process, frequently imparts invasive properties in Glioblastoma Multiforme (GBM), which leads to a poor prognosis. Cells lose apical-basal polarity, cell-cell connections, and/or chemo-resistance during EMT, which can result in the spread of cancer and the acquisition of additional stem cell-like traits. It is unclear how organelle dynamics influence EMT in this respect. The interaction between cytoskeletal and mitochondrial regulators governing GBM cell EMT is explored in this article. Results and DiscussionIn GBM cells, we observed that TGF-{beta}-induced EMT led to a proliferative arrest, which was accompanied by a fragmented mitochondrial morphology, elevated expression of fission markers such as DRP1, MFF, and FIS1, and most importantly, localization of mitochondria near the cell boundaries. An increase in mitochondrial ROS accompanied this, but their functional status was indicated by a higher oxygen consumption rate (OCR). Additionally, cytoskeleton re-distribution and EMT reversal were the outcomes of si-RNA-mediated elimination of the fission-marker DRP-1 or pharmacological inhibition of fission by Mdivi-1. On the other hand, drugs that disrupt the cytoskeleton, shifted the spatial distribution of mitochondria to the perinuclear area, which had an adverse effect on EMT. Notably, it was shown that RhoA, a protein that helps organize the actin cytoskeleton, co-immunoprecipitates with DRP1 and governs both cytoskeletal dynamics and mitochondrial fission in its presence. ConclusionOur research sheds substantial insight on the current interactions between the cytoskeleton and mitochondrial spatial dynamics that control EMT in GBM cells, which may have significant therapeutic implications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/694080v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@81b796org.highwire.dtl.DTLVardef@3bec9aorg.highwire.dtl.DTLVardef@2a79c3org.highwire.dtl.DTLVardef@9ff14a_HPS_FORMAT_FIGEXP M_FIG C_FIG