Biology subjects

Holthusen, H.

Publications and source records attributed to Holthusen, H..

4 recordsLinked to original sources

bioRxiv2026

Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization

Proteostasis failure is a hallmark of stress and disease, yet how it compromises mitochondrial integrity remains unclear. Here, we identify mitochondrial protein import as a critical pathway linking proteostasis failure to mitochondrial injury. We show that Raptinal, previously characterized as a rapid inducer of apoptosis, impairs the folding of newly synthesized proteins rather than directly disrupting mitochondrial membranes. The resulting proteotoxic stress drives mitochondrial outer membrane permeabilization and intrinsic apoptosis independently of BCL-2 family pore-forming proteins. VBIT4, a compound commonly used to maintain mitochondrial integrity, inhibited this pathway, and chemical proteomics with a photoaffinity analogue implicated the TIM23 import machinery. Genetic or pharmacological inhibition of the TIM23-PAM axis suppressed mitochondrial permeabilization without affecting canonical BAX-BAK-dependent apoptosis. These findings establish that mitochondrial protein import couples translation-associated proteotoxic stress to mitochondrial injury and identify regulation of import flux as a determinant of mitochondrial integrity during proteostasis failure.

cell biology↗

bioRxiv2025

The mechanics and physics of tofu: Understanding hydrated soft solids through feature networks

Tofu remains one of the worlds most important plant-based foods, famous for its cultural legacy, nutritional benefits, and environmental sustainability. Made up of only two ingredient-soy beans and water-it has nourished people for centuries; yet, its rheology remains incompletely understood. Here, we use tofu as a minimal model system to study how composition governs the mechanics and physics of hydrated soft solids. We perform over a hundred controlled compression tests on silken, firm, and extrafirm tofu, and observe a strong nonlinearity, a pronounced viscoelasticy, and a more than ten-fold increase in stress with only six percent decrease in water content. We demonstrate that automated model discovery can identify inelastic constitutive laws that accurately capture these unique characteristics across multiple loading magnitudes and rates. The discovered models autonomously separate elastic and inelastic mechanisms and reveal that tofu elasticity depends primarily on the second isochoric invariant, while tofu inelasticity depends on a combination of the second and third deviatoric invariants. This functional form is universal across all three tofu types, but scales in magnitude with water content. Our new water-content-based feature network reveals that this correlation in not linear, as assumed by traditional bi-phasic theories, but rather highly non-linear and sensitive to the individual model terms. These results position tofu as a quantitative benchmark for nonlinear poroviscoelastic solids and demonstrate how physics-informed machine learning can uncover the constitutive structure of hydrated soft materials. Our source code and examples are available at https://doi.org/10.5281/zenodo.16993236.

biophysics↗

bioRxiv2025

Mitochondrial proteostatic stress disrupts mitoribosome biogenesis and translation

Protein aggregation in various cellular compartments is a hallmark of proteostasis impairment linked to aging and numerous pathologies. Mitochondrial function depends on a balanced interplay of proteins imported from the cytosol as well as those synthesized on mitochondrial ribosomes (mitoribosomes). Here, we reveal an unexpected susceptibility of mitoribosome biogenesis to organellar proteostatic stress. Importing aggregation-prone proteins into yeast and human mitochondria triggered a chain of detrimental events involving extensive co-aggregation of newly-imported mitoribosome subunits and other RNA-binding proteins, as well as local disruption of mitochondrial cristae morphology. As a result, mitoribosome assembly and mitochondrial translation were severely impaired, leading to respiratory deficiency and, ultimately, loss of mitochondrial DNA. Surprisingly, dysfunction of mitochondrial HSP60 phenocopied the ribosome biogenesis defect and inhibition of translation, indicating a pronounced chaperone dependence of mitoribosome proteins. Declining mitochondrial translation likely contributes to aging and diseases associated with deficiencies in mitochondrial protein quality control machinery.

cell biology↗

bioRxiv2022

The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimers disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the AAA+ chaperone VCP is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with Hsp70 and the ubiquitin-proteasome machinery. Inhibition of VCP activity stabilizes large Tau aggregates, and is accompanied by a reduction in the amount of Tau species competent of prion- like aggregate seeding in recipient cells. Thus, disaggregation by VCP generates seeding-active Tau as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.

cell biology↗