Tubulin βII and βIII Isoforms as the Regulators of VDAC Channel Permeability in Health and Disease

Abstract

In recent decades, there have been several models describing the relationships between the cytoskeleton and the bioenergetic function of the cell. The main player in these models is the voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. At the same time, high-energy phosphates are channeled out and directed to cellular energy transfer networks. Regulation of these energy fluxes is controlled by β-tubulin, bound to VDAC. It is also thought that β-tubulin‒VDAC interaction modulates cellular energy metabolism in cancer, e.g., switching from oxidative phosphorylation to glycolysis. In this review we focus on the described roles of unpolymerized αβ-tubulin heterodimers in regulating VDAC permeability for adenine nucleotides and cellular bioenergetics. We introduce the Mitochondrial Interactosome model and the function of the βII-tubulin subunit in this model in muscle cells and brain synaptosomes, and also consider the role of βIII-tubulin in cancer cells.

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

“…Our findings of the relatively low K m value for ADP for colorectal polyps suggest an early metabolic reprogramming towards the glycolytic phenotype with functional OXPHOS. The results of the current study confirm our previous findings, indicating that in cancer tissues, the regulation of MOM permeability to adenine nucleotides is different from that in normal cells [25,28,29]. Proteins that could regulate the VDAC permeability for adenine nucleotides in colonocytes and corresponding cancer cells are still unknown.…”

“…The possible candidates are βIII-tubulin and γ-tubulin. βIII-tubulin acts as a marker of cancer aggressiveness, and γ-tubulin formed meshwork has been shown to be associated with mitochondrial membranes [29,55,56]. However, the regulation of energy metabolism through control over metabolites and energy fluxes that pass through the MOM is only one aspect of the possible role of VDAC influencing carcinogenesis.…”

“…In the closed state, VDAC is impermeable to adenine nucleotides [26,27]. Several studies have shown that during carcinogenesis the VDAC permeability for ADP is altered [22,[28][29][30]. The cell-specific differences in K m (ADP) are likely due to specific structural and functional organization of energy metabolism.…”

Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells

“…In the heart, tubulins form a network which, together with plectin, desmin, and microfilament proteins (actin), creates a precise structural organization of cardiac cells. This organization is essential to sustain the cardiac contractile function, as well as for the regulation of energy supply and demand [19,[21][22][23]101,[113][114][115]. It is known that tubulin in vivo is dynamic, undergoing assembly/disassembly processes due to interchanges between its subunits.…”

“…Many cytoskeletal elements play a vital role in the structural and functional organization of mitochondria, including mitochondrial shape and morphology, dynamics, motility, and mitosis [13][14][15][16][17]. Most importantly, the interaction of mitochondria with some cytoskeletal proteins and their connections to voltage dependent anion channel (VDAC) can be involved in the coordination of mitochondrial function [18][19][20][21][22][23] (Figure 1). In the heart, mitochondrial bioenergetics and oxygen consumption are linearly dependent on the cardiac contractile activity [24,25] at rather stable concentration of the main mitochondrial regulator adenosine diphosphate (ADP), which is a central element in mitochondrial physiology.…”