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.

Keywords: brain; cancer; creatine kinase; hexokinase; mitochondria; oxidative muscle; oxidative phosphorylation; synaptosomes; tubulin; voltage-dependent anion channel (VDAC).

Figure 1

The Mitochondrial Interactosome (MI) and the role of tubulin in its regulation. In the MI of oxidative muscle cells the tubulin C-terminal tail interacts with the mitochondrial voltage-dependent anion channel (VDAC) and restricts the diffusion of adenine nucleotides ATP and ADP through the channel. Tubulin-VDAC interaction does not interfere with creatine (Cr) and phosphocreatine (PCr) movement in or out of the mitochondria. Creatine is phosphorylated in the mitochondrial intermembrane space (IMS) by mitochondrial creatine kinase (MtCK). As the MtCK is located close to the adenine nucleotide translocase (ANT), the ATP produced in the mitochondrial matrix is quickly directed to MtCK reaction and ADP is transported back to the matrix. Due to this VDAC-tubulin interaction the energy-rich phosphate is directed to the CK energy transfer network and MtCK has become an important regulator of the ATP synthasome (consisting of the F_oF₁-ATPase, respiratory chain complexes, inorganic phosphate carrier (PIC) and ANT). Hexokinase (HK) can also bind to VDAC. The main task of this interaction is to guide the ATP produced in mitochondria to be available for glycolysis. In MI of cancer cells MtCK probably does not participate in the regulation of oxidative phosphorylation. To what extent and how tubulin (supposedly βIII-tubulin) and HK compete for binding on VDAC needs further investigation. MOM—mitochondrial outer membrane; MIM—mitochondrial inner membrane.