Biology subjects

Favier, J.

Publications and source records attributed to Favier, J..

8 recordsLinked to original sources

bioRxiv2026

Disentangling mucus rheology and transport efficiency in human airways

The protection of the respiratory tract relies on a layer of mucus that is transported along the epithelial surface by the beating of millions of microscopic cilia. This mechanism, called mucociliary clearance, is defective in chronic respiratory diseases. Since these pathologies alter mucus rheology, mucus transport efficiency is hypothesized to rely on its mechanical properties. Yet, this link is difficult to test due to limited experimental models. Here, we introduce an experimental framework that enables us to identify conditions associated with efficient mucus transport or arrest. Strikingly, we show that cilia are able to efficiently propel mucus with properties ranging from a viscoelastic fluid to an elastic solid, revealing that bulk mucus rheology is not the critical determinant of clearance failure. Instead, we demonstrate that the efficiency of mucociliary clearance is governed by the hydration of a thin fluid layer at the cilia-mucus interface. Finally, we use a hydrodynamic model informed by measurements on ciliary beat patterns to infer the properties of this critical layer under both transported and arrested mucus conditions. This work not only offers a novel understanding of the fundamental physical mechanism of mucus transport, but also provides a well-defined and quantitative assay to test effects of mucolytic agents or drugs on mucus clearance.

biophysics↗

bioRxiv2025

Robust ciliary flows protect early Xenopus embryos from pathogens independent of multiciliated cell patterning

During the early stages of development, the skin of the Xenopus embryo is covered by around two thousand evenly distributed multiciliated cells (MCCs). This striking spatial distribution is believed to maximise the generation of superficial flows at the scale of the embryo. However, the specific role of regular MCC distribution and the physiological function of vigorous ciliary activity remain elusive. We investigate the extent to which superficial flows provide protection against external pathogens before the immune system matures, by combining experimental and computational approaches. First, we cultivated epithelial explants in order to quantify the distribution of MCCs, beating frequencies, and three-dimensional fluid flows. We then use these data to validate a computational fluid dynamics model. Using this model, seeded with structural data from whole embryos, our simulations reveal that the collective ciliary beatings create a robust liquid shield along the embryonic flank, which is highly effective at clearing pathogens from the vicinity of the epithelial surface. Through parametric analyses, we further demonstrate that this protective function is remarkably resilient. Indeed, the effectiveness of pathogen clearance is primarily governed by the overall characteristic velocity of the cilia and is less affected by moderate variations in MCC density and spatial organisation. Our findings suggest that, rather than optimising energy consumption, the biological system prioritises functional robustness to ensure reliable protection.

biophysics↗

bioRxiv2025

Unbiased CRISPR Synthetic Lethal Screening for Genetic Vulnerabilities in Succinate Dehydrogenase (SDH)-loss Model of Paraganglioma

Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare neuroendocrine tumors for which no effective targeted therapies currently exist. To uncover new potential therapeutic targets, we performed an unbiased CRISPR-Cas9 genetic screen in immortalized mouse chromaffin cells (imCCs) with and without Sdhb loss. Our screen identified genes that differentially affect cell proliferation in Sdhb-deficient versus normal imCCs. Notably, several subunits of the transcriptional Mediator complex emerged as potential tumor suppressors, as their loss selectively promoted growth of Sdhb-deficient cells. Most strikingly, we found that the neddylation pathway--required for ubiquitin-mediated selective protein degradation--plays a critical role in controlling cell growth and survival in Sdhb-deficient imCCs. Specifically, loss of the neddylation regulator Ube2m led to increased proliferation, while loss of Ube2f suppressed growth of Sdhb-deficient imCCs. Consequently, global neddylation inhibitor MLN4924 (Pevonedistat) and UBE2F-CRL5 axis inhibitor HA-9104 were shown to downregulate neddylation, suppressing UBE2F activity and selectively inhibiting growth of Sdhb-deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability in this cell culture model of SDH-deficient PPGL.

biochemistry↗

bioRxiv2025

Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts

BackgroundThe tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells. MethodsWe comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid {beta}-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition. ResultsSDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins. ConclusionsSDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. These findings reveal cell type-specific adaptations to SDH loss. The plasticity of the response of imCCs may underlie the tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.

cancer biology↗

bioRxiv2021

Longitudinal to transverse metachronal wave transitions in an in-vitro model of ciliated bronchial epithelium

Myriads of cilia beat on ciliated epithelia, which are ubiquitous in life. When ciliary beats are synchronized, metachronal waves emerge, whose direction of propagation depends on the living system in an unexplained way. We show on a reconstructed human bronchial epithelium in-vitro that the direction of propagation is determined by the ability of mucus to be transported at the epithelial surface. Numerical simulations show that longitudinal waves maximise the transport of mucus while transverse waves, observed when the mucus is rigid and still, minimize the energy dissipated by the cilia.

biophysics↗

bioRxiv2020

Hydrodynamic model of directional ciliary-beat organization in human airways

In the lung, the airway surface is protected by mucus, whose transport and evacuation is ensured through active ciliary beating. The mechanisms governing the long-range directional organization of ciliary beats, required for effective mucus transport, are much debated. Here, we experimentally show on human bronchial epithelium reconstituted in-vitro that the dynamics of ciliary-beat orientation is closely connected to hydrodynamic effects. To examine the fundamental mechanisms of this self-organization process, we build a two-dimensional model in which the hydrodynamic coupling between cilia is provided by a streamwise-alignment rule governing the local orientation of the ciliary forcing. The model reproduces the emergence of the mucus swirls observed in the experiments. The predicted swirl sizes, which scale with the ciliary density and mucus viscosity, are in agreement with in-vitro measurements. A transition from the swirly regime to a long-range unidirectional mucus flow allowing effective clearance occurs at high ciliary density and high mucus viscosity. In the latter case, the mucus flow tends to spontaneously align with the bronchus axis due to hydrodynamic effects.

biophysics↗

bioRxiv2019

Active mucus-cilia hydrodynamic coupling drives self-organisation of human bronchial epithelium

The respiratory tract is protected by mucus, a complex fluid transported along the epithelial surface by the coordinated beating of millions of microscopic cilia, hence the name of mucociliary clearance. Its impairment is a strong marker of severe chronic respiratory diseases. Yet, the relationship between ciliary density and the spatial scale of mucus transport, as well as the mechanisms that drive ciliary-beat orientations during ciliogenesis are much debated. Here, we show on polarized human bronchial epithelia that mucus swirls and circular orientational order of the underlying ciliary beats emerge and grow during ciliogenesis, until a macroscopic mucus transport is achieved for physiological ciliary densities. By establishing that the macroscopic ciliary-beat order is lost and recovered by removing and adding mucus respectively, we demonstrate that cilia/mucus hydrodynamic interactions govern the collective dynamics of ciliary-beat directions. We propose a two-dimensional model that predicts a phase diagram of mucus transport in accordance with the experiments. It paves the way to a predictive in-silico modeling of bronchial mucus transport in health and disease.

biophysics↗

bioRxiv2018

A new threat identified in the use of SDHIs pesticides targeting the mitochondrial succinate dehydrogenase enzyme

Succinate dehydrogenase inhibitors (SDHIs) are now widely used worldwide as fungicides to limit the proliferation of molds in cereal crops, or to better preserve fruits, vegetables, and seeds from these molds, as well as to facilitate the lawn care for public spaces and golf courses. According to the companies that produce them, the SDHIs quite specifically inhibit the activity of the succinate dehydrogenase in the molds. We here establish that these inhibitors readily inhibit the earthworm and the human enzyme, raising a new concern on the danger of their large scale utilization in agriculture. This is all the more worrying as we know that the loss of function, partial or total, of the SDH activity caused by genetic variants causes severe human neurological diseases, or leads to the development of tumors and/or cancers.

ecology↗