Biology subjects

Fukui, M.

Publications and source records attributed to Fukui, M..

5 recordsLinked to original sources

bioRxiv2026

Filament-resolved simulations reproduce self-organization of lamellipodia and filopodia

The dynamic assembly of actin filaments underlies diverse cellular morphologies such as lamellipodia, filopodia, and reticulated networks. However, how filament-scale interactions among actin-binding proteins produce distinct actin architectures remains unclear. We developed a filament-resolved computational model of actin self-organization regulated by the Arp2/3 complex and fascin. Individual F-actin filaments are represented as elastic chains, and their stochastic polymerization, Arp2/3-mediated branching, and fascin-mediated crosslinking and bundling are explicitly modeled. The simulations reproduce three actin architectures observed in minimal reconstitution experiments, including lamellipodia-like branched networks, filopodia-like bundled protrusions, and reticulated meshworks, as a function of Arp2/3 and fascin concentrations. We quantify these regimes using actin density, orientational order, and spikiness, which robustly separate the three morphologies across conditions. To connect filament organization to shape change, we further couple the actin network to membrane deformation using a phase-field formulation. This coupling shows how localized remodeling concentrates load to drive pseudopodial protrusions, whereas highly branched networks distribute stresses and stabilize rounded shapes. The model links molecular interactions to emergent architecture and cell-scale morphodynamics.

biophysics↗

bioRxiv2025

Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice

Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously demonstrated that a treatment of inducing Plagl2, a zinc finger transcription factor gene, and antagonizing Dyrk1a, a gene associated with Down syndrome, referred to as iPaD, can functionally rejuvenate aged neural stem cells (NSCs), thereby enhancing neurogenesis and improving cognition in aged mice. Here, we found that NSC-specific iPaD treatment effectively activated neurogenesis, reduced amyloid-{beta} deposition, and improved cognitive function in Alzheimers disease model mice. Transcriptomic analysis revealed widespread significant changes in gene expression in the hippocampus following iPaD treatment. The upregulated genes included those associated with the activation of astrocytes and microglia involved in amyloid-{beta} clearance, while the downregulated genes included several that are upregulated in Alzheimers disease patients, but whose roles in disease progression remain unclear. Among the latter genes, knockdown of Prkag2, a gene encoding protein kinase AMP-activated non-catalytic subunit gamma 2, in the hippocampus most effectively enhanced neurogenesis and reduced amyloid-{beta} accumulation. Notably, both iPaD treatment and Prkag2 knockdown activated AMP-activated protein kinase signaling, thereby upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimers disease.

neuroscience↗

bioRxiv2025

Isolation of Crenothrix bacteria reveals the distinct ecophysiologies of filamentous methanotrophs and adaptations to redox stress

At the dawn of modern microbiology, Cohn observed abundant filamentous bacteria in drinking water wells that he named Crenothrix polyspora. Subsequent research has revealed the methanotrophic metabolism of Crenothrix bacteria and their disproportionately high activity in stratified lakes compared to unicellular strains, yet laboratory cultivation has proven elusive, leaving the ecophysiology of Crenothrix bacteria largely unknown. Here we report the isolation of two methanotroph strains of the "lacustrine Crenothrix" clade from an iron-rich wetland and reveal their highly unique cell biologies and potential ecological roles. Using physiological approaches, we demonstrate that the strains perform a microaerobic methane metabolism while growing distinct filaments having wide and directionally oriented connective structures. The strains further have broad genomic repertoires for addressing redox stress that we show are uniquely associated with lacustrine Crenothrix compared to related methanotrophs based on genome data. Aligning with laboratory observations, we identify lacustrine Crenothrix bacteria along potential redox gradients in the wetland at iron-rich snow sites, and we further detect such bacteria in diverse global ecosystems based on public metagenome searches. Together, our data strongly point to an ecophysiology of lacustrine Crenothrix bacteria that is tightly linked to redox stress, and we propose these bacteria may uniquely store or share metabolic intermediates via their filamentous lifestyle to thrive under such conditions. Our results provide a fresh view of the diversity, evolution, and ecology of aerobic methanotrophs, connecting over 150 years of microbiology research opening vast new opportunities to probe bacterial adaptations that drive global methane cycling under redox stress.

microbiology↗

bioRxiv2024

Machine learning-guided reconstruction of cytoskeleton network from Live-cell AFM Images

How actin filaments (F-actins) are dynamically reorganized in motile cells at the level of individual filaments is an open question. To this end, we developed a high-speed atomic force microscopy (HS-AFM) to live-imagine intracellular dynamics of the individual F-actins. However, noise and low resolution made it difficult to fully recognize individual F-actins in the HS-AFM images. To tackle this problem, we developed a new machine learning method that quantitatively recognizes individual F-actins. The method estimates F-actin orientation from the image while improving the resolution. We found that F-actins were oriented at {+/-}35{degrees} toward the membrane in the lamellipodia, which is consistent with Arp2/3 complex-induced branching. Furthermore, in the cell cortex our results showed non-random orientation at four specific angles, suggesting a new mechanism for F-actin organization demonstrating the potential of our newly developed method to fundamentally improve our understanding of the structural dynamics of F-actin networks.

biophysics↗

bioRxiv2022

Liver lipophagy ameliorates nonalcoholic steatohepatitis through lysosomal lipid exocytosis

Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes via lysosomal exocytosis, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.

cell biology↗