beta III-Tubulin Structural Domains Regulate Mitochondrial Network Architecture in an Isotype-Specific Manner

beta III-tubulin is a neuronal microtubule protein that is aberrantly expressed in epithelial cancers. The microtubule network is implicated in regulating the architecture and dynamics of the mitochondrial network, although the isotype-specific role for beta-tubulin proteins that constitute this microtubule network remains unclear. High-resolution electron microscopy revealed that manipulation of beta III-tubulin expression levels impacts the volume and shape of mitochondria. Analysis of the structural domains of the protein identifies that the C-terminal tail of beta III-tubulin, which distinguishes this protein from other beta-tubulin isotypes, significantly contributes to the isotype-specific effects of beta III-tubulin on mitochondrial architecture. Mass spectrometry analysis of protein-protein interactions with beta-tubulin isotypes identifies that beta III-tubulin specifically interacts with regulators of mitochondrial dynamics that may mediate these functional effects. Advanced quantitative dynamic lattice light sheet imaging of the mitochondrial network reveals that beta III-tubulin promotes a more dynamic and extended reticular mitochondrial network, and regulates mitochondrial volume. A regulatory role for the beta III-tubulin C-terminal tail in mitochondrial network dynamics and architecture has widespread implications for the maintenance of mitochondrial homeostasis in health and disease.