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Altered Skeletal Muscle Microtubule‐Mitochondrial Voltage Gated‐Dependent Anion Channel (VDAC) 2 Binding is Related to Bioenergetic Impairments after Paclitaxel but not Vinblastine Chemotherapies
Author(s) -
Ramos Sofhia V,
Hughes Meghan C,
Perry Christopher GR
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.868.7
Subject(s) - voltage dependent anion channel , vinblastine , bioenergetics , mitochondrion , tubulin , mitochondrial permeability transition pore , microbiology and biotechnology , paclitaxel , microtubule , chemistry , biology , biochemistry , biophysics , programmed cell death , apoptosis , bacterial outer membrane , genetics , escherichia coli , chemotherapy , gene
Rationale Muscle weakness in response to chemotherapy is thought to be related to mitochondrial dysfunction. However, the underlying mechanisms by which chemotherapy alters mitochondrial bioenergetics remain unknown, but are likely unique to different types of these cytotoxic compounds. Taxanes (eg. Paclitaxel) and vinka alkaloids (eg. Vinblastine) prevent cancer cell mitosis by stabilizing and destabilizing microtubules, respectively. In mature muscle fibres (ie. non‐mitotic), microtubules are thought to regulate mitochondrial bioenergetics by directly binding the ADP/ATP exchanger voltage dependent anion channel (VDAC) on the outer mitochondrial membrane. As ADP simultaneously regulates oxidative phosphorylation and oxidant generation by modulation of membrane potential, we hypothesized that manipulating microtubule architecture with paclitaxel and vinblastine would alter tubulin‐VDAC interactions and influence ADP‐dependent respiration and H 2 O 2 emission. As VDAC is thought to be involved in the formation of the mitochondrial permeability transition pore (mPTP) under calcium stress, we also hypothesized that these compounds would alter mitochondrial calcium retention capacity (CRC) required for mPTP formation. Methods : Single muscle fibres and permeabilized fibre bundles were isolated from rat extensor digitorum longus muscles and incubated in paclitaxel (2hr) and vinblastine (1hr) at 4°C prior to assessing protein‐protein interactions (proximity ligation assay) and mitochondrial bioenergetics. Results Paclitaxel increased both a‐ ( p=0.01 ) and bII‐tubulin ( p=0.01 ) interactions with VDAC2 which was associated with a decreased ability of ADP to attenuate H 2 O 2 emission (main effect, p=0.0006 ) despite no effect on ADP‐stimulated respiration or CRC. In contrast, vinblastine had no effect on the amount of a‐ and bII‐tubulin interactions with VDAC but still increased ADP‐stimulated respiration (main effect, p= 0.006 ), decreased the ability of ADP to attenuate H 2 O 2 emission (main effect, p=0.002 ) and sensitized mPTP formation as demonstrated by reduced CRC ( p=0.04 ). Conclusion and Discussion The results demonstrate that both microtubule stabilizing and destabilizing chemotherapies cause diverse mitochondrial dysfunctions which may provide insight into their detrimental effects on muscle function. Collectively, these findings partially support the tubulin‐VDAC model of regulating mitochondrial bioenergetics but suggests that microtubule architecture may also regulate mitochondrial function in mature muscle fibres through additional mechanisms. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. S.V.R was supported by Ontario Graduate Scholarship. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .