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.
Highlights
The beta-tubulins, as subunits of tubulin, the building block of microtubules (MTs), are a widespread cytoskeletal proteins present in all eukaryotic cells
Removal of C-terminal tyrosine from the α-tubulin C-terminal tails (CTTs) peptide-albumin construct significantly enhanced voltage-dependent anion channel (VDAC) closure activity of the peptide, and activation is reversed by subsequent removal of the of the glutamic acid penultimate to the tyrosine [10]. These results indicate that the interaction between the tubulin dimer and VDAC is determined by the CTTs and that a small change in sequence or post-translational modification, especially tyrosination/detyrosination, of these tails results in substantial changes to the VDAC closure
As a consequence of the βII-tubulin–VDAC interaction the regulation of mitochondrial respiration by creatine in adult cardiomyocytes is accomplished via cooperatively functioning proteins such as ATP synthasome consisting of ATP synthase, respiratory system and inorganic phosphate transporter, mitochondrial creatine kinase (MtCK), VDAC and tubulin that form a supercomplex called Mitochondrial Interactosome (Figure 1) [11,12,45]
Summary
The beta-tubulins, as subunits of tubulin (αβ-tubulin heterodimers), the building block of microtubules (MTs), are a widespread cytoskeletal proteins present in all eukaryotic cells. Gastrocnemius white is associated with high MOM permeability for adenine nucleotides (low apparent KmADP) [30] These results support a model whereby energy metabolism is directly linked to the highly organized intracellular architecture in cardiomyocytes and slow-twitch skeletal muscles; this βII-tubulin isoform may participate in the regulation of VDAC permeability in oxidative muscle cells. As a consequence of the βII-tubulin–VDAC interaction the regulation of mitochondrial respiration by creatine in adult cardiomyocytes is accomplished via cooperatively functioning proteins such as ATP synthasome consisting of ATP synthase, respiratory system and inorganic phosphate transporter, MtCK, VDAC and tubulin that form a supercomplex called Mitochondrial Interactosome (Figure 1) [11,12,45].
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