Ramos 2019 Am J Physiol Cell Physiol
|Ramos SV, Hughes MC, Perry CGR (2019) Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies. Am J Physiol Cell Physiol [Epub ahead of print].|
Abstract: Microtubule-targeting chemotherapies are linked to impaired cellular metabolism which may contribute to skeletal muscle dysfunction. However, the mechanisms by which metabolic homeostasis is perturbed remains unknown. Tubulin, the fundamental unit of microtubules, has been implicated in the regulation of mitochondrial-cytosolic ADP/ATP exchange through its interaction with the outer membrane voltage-dependent anion channel (VDAC). Based on this model, we predicted that disrupting microtubule architecture with the stabilizer paclitaxel and destabilizer vinblastine would impair skeletal muscle mitochondrial bioenergetics. Here we provide in vitro evidence of a direct interaction between both a-tubulin and bII-tubulin with VDAC2 in un-treated single extensor digitorum longus fibres. Paclitaxel increased both a- and bII-tubulin-VDAC2 interactions whereas vinblastine had no effect. Utilizing a permeabilized muscle fiber bundle preparation that retains the cytoskeleton, paclitaxel treatment impaired the ability of ADP to attenuate H2O2 emission, resulting in greater H2O2 emission kinetics. Despite no effect on tubulin-VDAC2 binding, vinblastine still altered mitochondrial bioenergetics through a surprising increase in ADP-stimulated respiration while also impairing ADP-suppression of H2O2 and increasing mitochondrial susceptibility to calcium-induced formation of the pro-apoptotic permeability transition pore. Collectively, these results demonstrate that altering microtubule architecture with chemotherapeutics disrupts mitochondrial bioenergetics in skeletal muscle. Altered tubulin-VDAC binding with paclitaxel supports the model that microtubules regulate mitochondria by altering ADP's governance of bioenergetics, whereas vinblastine may act through an alternative mechanism associated with decreased microtubule abundance in skeletal muscle.
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Rat Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: OXPHOS Pathway: N HRR: Oxygraph-2k