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en: Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line.

en: Drug resistance limits the efficacy of chemotherapy and targeted cancer treatments, calling for the identification of druggable targets to overcome it. Here we show that the mitochondria-shaping protein Opa1 participates in resistance against the tyrosine kinase inhibitor gefitinib in a lung adenocarcinoma cell line. Respiratory profiling revealed that oxidative metabolism was increased in this gefitinib-resistant lung cancer cell line. Accordingly, resistant cells depended on mitochondrial ATP generation, and their mitochondria were elongated with narrower cristae. In the resistant cells, levels of Opa1 were increased and its genetic or pharmacological inhibition reverted the mitochondrial morphology changes and sensitized them to gefitinib-induced cytochrome c release and apoptosis. In vivo, the size of gefitinib-resistant lung orthotopic tumors was reduced when gefitinib was combined with the specific Opa1 inhibitor MYLS22. The combo gefitinib-MYLS22 treatment increased tumor apoptosis and reduced its proliferation. Thus, the mitochondrial protein Opa1 participates in gefitinib resistance and can be targeted to overcome it.

en: Cell Death & Disease

ja: Cell Death & Disease


en: Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth.

en: Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC.

en: Journal of Experimental & Clinical Cancer Research


en: Unidirectional cooperative binding of fimbrin actin-binding domain 2 to actin filament.

en: Fimbrin forms bundles of parallel actin filaments in filopodia, but it remains unclear how fimbrin forms well-ordered bundles. To address this issue, we focused on the cooperative interaction between the actin-binding domain of fimbrin and actin filaments. First, we loosely immobilized actin filaments on a glass surface via a positively charged lipid layer and observed the binding of GFP-fused actin-binding domain 2 of fimbrin using fluorescence microscopy. The actin-binding domain formed low-density clusters with unidirectional growth along actin filaments. When the actin filaments were tightly immobilized to the surface by increasing the charge density of the lipid layer, cluster formation was suppressed. This result suggests that the propagation of cooperative structural changes of actin filaments evoked by binding of the actin-binding domain was suppressed by a strong physical interaction with the glass surface. Interestingly, binding of the fimbrin actin-binding domain shortened the length of loosely immobilized actin filaments. Based on these results, we propose that fimbrin-actin interactions accompanied by unidirectional long-range allostery help the formation of well-ordered parallel actin filament bundles.

en: Biochemical and Biophysical Research Communications


en: Conformational diversity of dynactin sidearm and domain organization of its subunit p150.

en: Dynactin is a principal regulator of the minus-end directed microtubule motor dynein. The sidearm of dynactin is essential for binding to microtubules and regulation of dynein activity. Although our understanding of the structure of the dynactin backbone (Arp1 rod) has greatly improved recently, structural details of the sidearm subcomplex remain elusive. Here, we report the flexible nature and diverse conformations of dynactin sidearm observed by electron microscopy. Using nanogold labeling and deletion mutant analysis, we determined the domain organization of the largest subunit p150 and discovered that its coiled-coil (CC1), dynein-binding domain, adopted either a folded or an extended form. Furthermore, the entire sidearm exhibited several characteristic forms, and the equilibrium among them depended on salt concentrations. These conformational diversities of the dynactin complex provide clues to understanding how it binds to microtubules and regulates dynein.

en: Molecular Biology of the Cell

ja: Molecular Biology of the Cell