Biology subjects

Brodesser, S.

Publications and source records attributed to Brodesser, S..

10 recordsLinked to original sources

bioRxiv2026

A Neuronally Active Bacterial Siderophore Manipulates Host Behavior and Longevity

Aging populations face a growing burden of neurodegenerative disease and behavioral decline. The microbiota is increasingly implicated in host physiology, highlighting an urgent need to understand how gut microbes modulate brain function and late life health. Here, we develop a high-throughput microbe-host screening platform to systematically dissect how bacterial genes shape organismal behavior. Using the Escherichia coli Keio library of 3,985 distinct non-essential single-gene deletion mutants in combination with Caenorhabditis elegans, we quantitatively profiled 768 behavioral features per bacterial clone and uncovered a coherent module of bacterial genes involved in iron homeostasis that robustly reprogrammed host behavior. Bacterial omics analyses revealed that alterations in iron homeostasis amplify siderophore production in a TCA cycle-dependent manner, and loss of enterobactin biosynthesis abolished the bacteria-induced changes in worm movement. Transcriptional, molecular and functional studies demonstrated that bacterial enterobactin activates host neuromuscular responses to shape both lifespan and healthspan in a manner dependent on the mitochondrial unfolded protein response. Thermal proteome profiling identified mitochondrial glutaryl-CoA dehydrogenase and the electron-transfer flavoproteins A and B as enterobactin-binding targets that control mitochondrial function. Finally, genetic manipulation of neuronal mitochondrial and cytosolic reactive oxygen species via superoxide dismutase and catalase revealed that redox state modulates enterobactin-driven changes in movement and lifespan through the secretin-family GPCR neuropeptide receptor PDFR-1. Together, these findings establish microbial enterobactin as a non-canonical neurotransmitter regulating neuronal mitochondrial function, behavior and aging, defining a gut bacteria-brain axis with broad implications for maintaining late-life health.

animal behavior and cognition↗

bioRxiv2026

Restoring Antibiotic Sensitivity via Metabolic Pathway Manipulation in Pseudomonas aeruginosa

Stopping antimicrobial multidrug resistance (AMR) is essential to maintain the efficacy of current treatments and sustain modern medicine, but current control relies on a coordinated One Health approach involving stewardship, infection prevention and other control measures, without direct actionable mechanisms against resistance itself. Here, integrating proteomics and metabolomics with high-throughput Caenorhabditis elegans infection models, we show that unique synergy of biotin biosynthesis inhibition with metformin uncouples virulence from bacterial viability shutting down major Pseudomonas aeruginosa (PA) virulence mechanisms that impair host survival. Under directed evolution induced by central carbon metabolic stress, laboratory and clinical PA strain isolates acquire mutations in the MexAB-OprM multidrug efflux pump, leading to reversal of the AMR phenotype and restored susceptibility to multiple legacy and last-resort antibiotics such as meropenem. Our findings reveal a previously unexploited vulnerability in PA, its co-dependence on biotin biosynthesis and energy metabolism for virulence and resistance. This work establishes a conceptual framework in which metabolic co-targeting can abolish pathogenesis and drive reversal of antimicrobial resistance. It lays the foundation for first-in-class, non-antibiotic PA-selective anti-virulence and resistance-reversing therapies, key to extending the lifesaving duration of existing antibiotics.

microbiology↗

bioRxiv2026

Gut Microbiota Fuel Aging Induced by Mitochondrial Dysfunction

Aging is characterized by hallmarks whose mechanistic interdependencies remain poorly defined. Here, we investigate the bi-directional communication between gut microbiota and host mitochondria in the context of immune regulation, healthspan and lifespan. Using a mitochondrial dysfunction PolgAmut mouse model of accelerated aging, we tested the role of mitochondrial dysfunction in modulating microbial homeostasis and aging. We find that impairment of mitochondrial function hastens the decline of microbiota structure over time and induces immune dysregulation and inflammation through metabolic reprogramming of the myeloid immune subset. Further, we find that gut microbiota drives a paradoxical energy state by reducing mitochondrial function systemically while simultaneously driving energy-intensive programs including immune remodelling and protein synthesis, through mTOR signaling. Thus, aging emerges from the progressive imbalance between microbiota-driven energetic demand and declining mitochondrial energy supply. We postulate that microbiota promote host early-life fitness, at the cost of amplifying metabolic stress and inflammation later in life.

microbiology↗

bioRxiv2024

Pathogenesis of mtDNA point mutation m.10191T>C affecting complex I function is a multifactorial process leading to metabolic remodeling of mitochondria

Inherited mitochondrial disorders are of multiple genetic origins and may lead to a broad range of frequently severe disease phenotypes. Yet, the correlation between molecular causes and clinical presentations is poorly understood. To address this conundrum, we thoroughly investigated the consequences of the well-known pathogenic mitochondrial DNA mutation m.10191T>C. The mutation changes serine-45 in subunit ND3 of respiratory chain complex I to proline and causes Leigh syndrome, which is one of the most devastating mitochondrial diseases. Human mitochondria carrying the mutation ND3S45P retained 30-40% of complex I activity and oxidative phosphorylation capacity. In stark contrast, intact mutant cells exhibited only minimal oxygen consumption and a massively increased NADH/NAD+ ratio. Since the energy barrier for the Active/Deactive transition of complex I was reduced by [~]20 kJ{middle dot}mol-1 in mutant cells, we concluded that complex I was shut-off by malfunctioning of an as yet unknown regulatory pathway. Comprehensive analysis of the mitochondrial complexome of cybrids, patient fibroblasts and muscle biopsies rendered other causes for the accumulation of NADH unlikely. The complexome datasets provide a rich resource for further studies to discover possible additional factors involved in regulating complex I. We propose that the derailed regulation of complex I is the main culprit leading to NADH accumulation and eventually the severity of the disease phenotype caused by mutation ND3S45P.

biochemistry↗

bioRxiv2024

ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway

Complexes of ERLIN1 and ERLIN2 form large ring-like cup-shaped structures on the endoplasmic reticulum (ER) membrane and serve as platforms to bind cholesterol and E3-ubiquitin ligases, potentially defining functional nanodomains. Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 and RNF170. We identify a luminal N-terminal conserved region in TMUB1 and RNF170 required for this interaction. Three-dimensional modelling shows that this conserved motif binds the SPFH domain of two adjacent ERLIN subunits at different interfaces. Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia (HSP). By using omics approaches in combination with phenotypic characterisation of cells lacking both ERLINs, we demonstrate a role for ERLIN scaffolds in maintaining cholesterol levels in the ER by favouring transport to the Golgi over esterification, thereby regulating Golgi morphology and the secretory pathway.

cell biology↗

bioRxiv2024

Sphingolipid metabolism orchestrates the establishment of the adult hair follicle stem cell niche to control skin homeostasis

Bioactive sphingolipids serve as an essential building block of membranes, forming a selective barrier that ensures subcellular compartmentalization and facilitates cell type-specific intercellular communication through regulation of the plasma membrane receptor repertoire. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem-cell specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 in the epidermis prevents the effective development of the adult hair follicle bulge stem cell (HFSCs) niche due to altered differentiation trajectories of HFSC precursors towards upper hair follicle and inner bulge fates. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids in HFSCs associated with hyperactivity of canonical Wnt signaling. Impaired HFSC niche establishment leads to disruption of hair follicle architecture and hair follicle barrier function, ultimately triggering a T helper cell 2 - dominated immune infiltration closely resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in epidermal stem cell homeostasis and the role of an intact stem cell niche in maintaining an intact skin barrier.

developmental biology↗

bioRxiv2022

Quantitative proteomics and lipidomics of TFG-deficient B cells provide insights into mechanisms of autophagic flux and plasma cell biology

The autophagy-flux-promoting protein TFG (Trk-fused gene) is up-regulated during B cell differentiation into plasma cells and supports survival of CH12 B cells. We hypothesized that quantitative proteomics analysis of CH12tfgKO B cells with intact or blocked autophagy-lysosome flux (via NH4Cl) will identify mechanisms of TFG-dependent autophagy, plasma cell biology and B cell survival. Analysis of CH12WT B cells in the presence of NH4Cl will identify proteins whose presence is continuously regulated by lysosomes independent of TFG. We determined hundreds of proteins to be controlled by TFG and/or NH4Cl. Notably, NH4Cl treatment alone increased the abundance of a cluster of cytosolic and mitochondrial translational proteins while it also reduced a number of proteins. Within the B cell relevant protein pool, BCL10 was reduced, while JCHAIN was increased in CH12tfgKO B cells. Furthermore, TFG regulated the abundance of transcription factors, such as JUNB, metabolic enzymes, such as the short-chain fatty acid activating enzyme ACOT9 or the glycolytic enzyme ALDOC. Gene ontology enrichment analysis revealed that TFG-regulated proteins localized to mitochondria and membrane-bounded organelles. Due to these findings we performed shotgun lipidomics of glycerophospholipids, uncovering that a particular phosphatidylethanolamine (PE) species, 32:0 PE, which lipidates LC3 most efficiently, was less abundant while phosphatidylglycerol (PG) was more abundant in CH12tfgKO B cells. In line with the role of PG as precursor for Cardiolipin (CL), the CL content was higher in CH12tfgKO B cells and addition of PG liposomes to B cells increased the amount of CL. We propose a role for TFG in B cell activation and plasma cell biology via regulation of proteins involved in germinal center and plasma cell development, such as BCL10 or JCHAIN, as well as in lipid homeostasis, mitochondria and metabolism.

immunology↗

bioRxiv2021

Organ protection by caloric restriction depends on activation of the de novo NAD+ synthesis pathway

Therapeutic strategies to treat acute kidney injury (AKI) are lacking in clinical practice. Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. A comparative transcriptome analysis of murine kidneys after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU strongly contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal the KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway as necessary for CR-associated maintenance of NAD+ levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans. These findings provide a valuable insight into the molecular mechanisms mediating protection upon preconditioning and point towards the de novo branch of NAD+ biosynthesis as a conserved target in nephroprotection.

physiology↗

bioRxiv2021

P2Y6 receptor signaling in natural killer cells impairs insulin sensitivity in obesity

Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance and have previously been shown to up-regulate the expression of the P2Y purinoreceptor 6 (P2Y6R) upon high fat diet (HFD)-induced obesity. Here, we reveal that NK cell-specific inactivation of the P2Y6R gene improves insulin sensitivity in obese mice and reduces the expression of chemokines in adipose tissue infiltrating NK-cells. Obese mice lacking P2Y6R specifically in NK cells exhibited a reduction in adipose tissue inflammation, exhibited improved insulin-stimulated suppression of lipolysis in adipose tissue and a reduction in hepatic glucose production, leading to an overall improvement of systemic insulin sensitivity. In contrast, myeloid lineage specific P2Y6R inactivation does not affect energy or glucose homeostasis in obesity. Collectively, we show that P2Y6R signaling in NK cells contributes to the development of obesity-associated insulin resistance and thus might be a future target for the treatment of obesity-associated insulin resistance and type 2 diabetes.

immunology↗

bioRxiv2021

Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells.

immunology↗