Tubulin-VDAC Interaction: Molecular Basis for Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy

Abstract

Tubulin is a well-established target of microtubule-targeting agents (MTAs), a widely used class of chemotherapeutic drugs. Yet, aside from their powerful anti-cancer efficiency, MTAs induce a dose-limiting and debilitating peripheral neurotoxicity. Despite intensive efforts in the development of neuroprotective agents, there are currently no approved therapies to effectively manage chemotherapy-induced peripheral neuropathy (CIPN). Over the last decade, attempts to unravel the pathomechanisms underlying the development of CIPN led to the observation that mitochondrial dysfunctions stand as a common feature associated with axonal degeneration. Concomitantly, mitochondria emerged as crucial players in the anti-cancer efficiency of MTAs. The findings that free dimeric tubulin could be associated with mitochondrial membranes and interact directly with the voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane strongly suggested the existence of an interplay between both subcellular compartments. The biological relevance of the interaction between tubulin and VDAC came from subsequent in vitro studies, which found dimeric tubulin to be a potent modulator of VDAC and ultimately of mitochondrial membrane permeability to respiratory substrates. Therefore, one of the hypothetic mechanisms of CIPN implies that MTAs, by binding directly to the tubulin associated with VDAC, interferes with mitochondrial function in the peripheral nervous system. We review here the foundations of this hypothesis and discuss them in light of the current knowledge. A focus is set on the molecular mechanisms behind MTA interference with dimeric tubulin and VDAC interaction, the potential relevance of tubulin isotypes and availability as a free dimer in the specific context of MTA-induced CIPN. We further highlight the emerging interest for VDAC and its interacting partners as a promising therapeutic target in neurodegeneration.

Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy

“…It may be that the irreversible accumulation of a soluble pool of D2 alters the composition of tubulin available for polymerization and in defects in tubulin/MT partitioning. Indeed, subtle changes in tubulin partitioning may impact mitochondria bioenergetics through tubulin interaction with VDACs with indirect consequences on motility ( 18 , 19 , 58 , 59 ). On the other hand, D2 may interfere with the adaptor machinery that recruits mitochondria to MT-dependent motors or mitochondria-anchoring proteins, leading to inhibition of motility ( 60 ).…”

Eribulin Activates the cGAS-STING Pathway via the Cytoplasmic Accumulation of Mitochondrial DNA

“…Previous studies have demonstrated that increases in cytoplasmic free tubulin heterodimers, similar to those we observe within 2 h of eribulin treatment (Figs. 1A, 2A), can directly interact with VDAC channels and disrupt mitochondrial membrane potential (Carre et al, 2002;Maldonado et al, 2010;Rovini, 2019). Additionally, other microtubule destabilizers, including the vinca alkaloids and combretastatin A-4, induce the expression of NOXA, which promotes the release and activation of BAX and BAK to form mitochondrial pores in non-cycling cells within the same timeframe where we observe an increase of cytoplasmic mtDNA with eribulin (Bates et al, 2013).…”

Oxaliplatin Depolarizes the IB4– Dorsal Root Ganglion Neurons to Drive the Development of Neuropathic Pain Through TRPM8 in Mice

“…The mechanisms of oxaliplatin-induced CIPN include DNA damage, mitochondrial dysfunction, calcium chelation, reactive oxygen species (ROS) production, and ion channel remodeling in dorsal root ganglion (DRG) neurons (Joseph et al, 2008;Descoeur et al, 2011;Boyette-Davis et al, 2015;Viatchenko-Karpinski et al, 2018;Rovini, 2019;Trecarichi and Flatters, 2019). For instance, transient receptor potential (TRP) channels expressed on DRG neurons such as TRPV1, TRPA1, and TRPM8 have been studied following the treatment of oxaliplatin (Chukyo et al, 2018).…”