Biology subjects

Breuer, M.

Publications and source records attributed to Breuer, M..

6 recordsLinked to original sources

bioRxiv2026

Ubp3 mediates dynamic deubiquitination of mitochondria upon induction of mitophagy

Ensuring quality and maintenance of mitochondria within eukaryotic cells is important for cellular fitness. One critical pathway that needs to be tightly controlled to achieve this is mitophagy, which is negatively regulated by the deubiquitinase Ubp3 in Saccharomyces cerevisiae. Here we show that beyond this established role of Ubp3, it is critical to mediate substantial temporal changes of the mitochondrial ubiquitin landscape during mitophagy. Isolated mitochondria displayed extensive ubiquitination under steady-state conditions, whereas rapamycin-mediated induction of mitophagy/autophagy led to a progressive elimination of mitochondrial ubiquitination. A systematic screening analysis revealed that Ubp3 and Ubp4 are crucial regulators of rapamycin-induced mitochondrial deubiquitination. Deletion of Bre5, a cofactor of Ubp3, or of the UBI4 gene, encoding Ubi4 required for mitophagy, did not impair deubiquitination of mitochondria during mitophagy, indicating that Ubp3 has additional functions. We further showed that Ubi4 acts epistatic to Ubp3 for regulating mitophagy, supporting that mitophagy does not simply depend on the extent of mitochondrial ubiquitination, but rather on specific ubiquitinated substrates. Consistent with the role of Ubp3 in vivo, purified Ubp3 or its catalytic domain alone were sufficient to efficiently deubiquitinate isolated mitochondria in vitro in a Bre5-independent manner. Together, these findings highlight Ubp3 as a prominent rheostat of mitochondrial ubiquitin remodelling, revealing mitochondrial ubiquitin storage and its dynamic release as another layer of stress regulation by ubiquitin-dependent quality control pathways.

cell biology↗

bioRxiv2025

Unravelling the intraspecific variation in drought responses in seedlings of European black pine (Pinus nigra J.F. Arnold)

O_LIUnderstanding intraspecific variation in drought tolerance is essential for predicting the adaptive capacity of forest species under climate change. Yet, the molecular basis of this variation remains poorly understood in ecologically and economically important conifers. C_LIO_LIWe integrated high-throughput phenotyping with metabolomics and transcriptomics under standardized soil drying to investigate drought responses across nine climatically distinct provenances of the conifer Pinus nigra. We tested whether drought tolerance--measured as decline in maximum quantum yield of the photosystem II (Fv/Fm)--varies among provenances, follows a climatic cline, and involves trade-off with growth. To identify the underlying molecular basis, we performed metabolomics and transcriptomics in four provenances representing contrasting drought tolerance. C_LIO_LIDrought tolerance varied significantly among provenances and was decoupled from growth, yet showed no differentiation along the climatic cline. Drought tolerant provenances differed from sensitive ones in both constitutive and drought-induced levels of flavonoid and diterpene metabolites. Transcriptomic profiles further highlighted provenance-specific differences in gene expression related to flavonoids. C_LIO_LIOur results demonstrate the utility of integrating automated phenotyping with molecular profiling to uncover the metabolic basis of drought adaptation, laying the groundwork for targeted studies on metabolite function and tolerance strategies in non-model conifers. C_LI

plant biology↗

bioRxiv2025

Metabolic task analysis reveals distinct metabotypes in end-stage dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is associated with shifts in cardiac metabolism. Those shifts are inconsistent between patients, possibly due to heterogeneity in DCM etiologies. Identifying metabolic subtypes, or metabotypes, in DCM patients may open personalized treatment opportunities. Developing a methodology to identify metabotypes would be a boon in this regard. Here, we describe a metabotyping pipeline, integrating advanced metabolic modeling methods optimized for cardiac research, to uncover these subtypes using widely available transcriptomics data. We applied our method to publicly available cardiac data of end-stage DCM patients and non-failing controls, identifying two metabotypes in the DCM group. These metabotypes are characterized by unique metabolic alterations, notably in calcium handling, amino-acid oxidation, and the pentose phosphate pathway. Strikingly, one metabotype exhibited a greater deviation from healthy controls, suggesting a greater metabolic contribution to its underlying etiology. Further transcriptome-wide analysis revealed immune-related differences between metabotypes, suggesting an interplay between inflammation, immune response and metabolism in these DCM subtypes. Our study uncovers cardiometabolic heterogeneity in DCM and underscores the potential of transcriptome-derived metabotyping in cardiovascular research.

systems biology↗

bioRxiv2024

Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity

Cellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity ({beta}-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells. Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples. Genes regulating stress responses - including transcription factors and genes controlling chromatin accessibility - are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner. We propose that senescence cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, TFs, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.

bioinformatics↗

bioRxiv2021

Metabolite Damage and Damage-Control in a Minimal Genome

Analysis of the genes retained in the minimized Mycoplasma JCVI-Syn3A genome established that systems that repair or preempt metabolite damage are essential to life. Several genes with known metabolite damage repair or preemption functions were identified and experimentally validated, including 5-formyltetrahydrofolate cyclo-ligase, CoA disulfide reductase, and certain hydrolases. Furthermore, we discovered that an enigmatic YqeK hydrolase domain fused to NadD has a novel proofreading function in NAD synthesis and could double as a MutT-like sanitizing enzyme for the nucleotide pool. Finally, we combined metabolomics and cheminformatics approaches to extend the core metabolic map of JCVI-Syn3A to include promiscuous enzymatic reactions and spontaneous side reactions. This extension revealed that several key metabolite damage-control systems remain to be identified in JCVI-Syn3A, such as that for methylglyoxal.

microbiology↗

bioRxiv2020

ComMet: A method for comparing metabolic states in genome-scale metabolic models

Being comprehensive knowledge bases of cellular metabolism, Genome-scale metabolic models (GEMs) serve as mathematical tools for studying cellular flux states in various organisms. However, analysis of large-scale (human) GEMs, still presents considerable challenges with respect to objective selection and reaction flux constraints. In this study, we introduce a model-based method, ComMet (Comparison of Metabolic states), for comprehensive analysis of large metabolic flux spaces and comparison of various metabolic states. ComMet allows (a) an in-depth characterisation of achievable flux states, (b) comparison of flux spaces from several conditions of interest and (c) identification and visualization of metabolically distinct network modules. As a proof-of-principle, we employed ComMet to extract the biochemical differences in the human adipocyte network (iAdipocytes1809) arising due to unlimited/blocked uptake of branched-chain amino acids. Our study opens avenues for exploring several metabolic conditions of interest in both microbe and human models. ComMet is open-source and is available at https://github.com/macsbio/commet.

systems biology↗