Biology subjects

Mulleder, M.

Publications and source records attributed to Mulleder, M..

6 recordsLinked to original sources

bioRxiv2026

Bro1-Mediated Trafficking Couples TOR Signalling to Cellular Metabolism and Longevity

Adaptation to nutrient availability requires coordination between growth control, metabolism, and intracellular trafficking. In eukaryotes, inhibition of Target of Rapamycin (TOR) signalling robustly promotes stress resistance and longevity, yet how reduced growth signalling is coupled to organelle dynamics and proteome remodelling remains unclear. Here, we identify the conserved ESCRT-associated protein Bro1 as a central integrator of TOR signalling, vacuolar trafficking, and metabolic adaptation. Using fission yeast, we show that Bro1 is required for normal lifespan and for the global proteomic reprogramming that accompanies TOR inhibition. In Bro1 mutant cells, repression of ribosome biogenesis is uncoupled from activation of catabolic, vacuolar, and metabolic pathways, resulting in an altered metabolic state characterised by elevated lipid metabolism and increased abundance of nutrient transporters. Mechanistically, Bro1 promotes TOR-dependent cargo deubiquitination, vacuolar trafficking, and turnover of plasma membrane hexose transporters and enables appropriate nuclear relocalisation of the transcriptional repressor Scr1. In the absence of Bro1, nutrient transporters persist at the cell surface despite TOR inhibition, conferring resistance to TOR inhibitors while impairing stress responses and reducing lifespan. Together, our findings establish Bro1 as a key coordinator linking ESCRT-mediated endosomal-vacuolar trafficking to TOR-dependent metabolic control. By coupling growth suppression to enhanced recycling and cellular maintenance, Bro1 enables the transition from growth to longevity-promoting states, revealing a mechanism connecting intracellular trafficking, metabolism, and ageing.

genetics↗

bioRxiv2025

Evolutionary rewiring of host metabolism and interferon signalling by SARS-CoV-2 variants

SARS-CoV-2 variants differ in transmissibility and immune evasion, but their effects on host-cell metabolism and signalling remain less defined. Using integrated transcriptomic, phosphoproteomic, and amino acid profiling in primary nasal epithelial cells, we compared early and late host responses to pre-Omicron variants (Alpha, Beta), Delta, and Omicron subvariants (BA.1, BA.5). Pre-Omicron strains broadly suppressed antiviral interferon-stimulated gene expression and reprogrammed metabolism by reducing mitochondrial oxidative phosphorylation and {beta}-oxidation. Delta infection was associated with extensive transcriptional and metabolic remodelling, characterised by activation of stress- and growth-related kinases and selective retention of biosynthetic amino acids, consistent with a host response to stress and viral modulation of interferon-associated signalling. In contrast, Omicron infection elicited a more restrained response dominated by cytokine and survival pathways, with limited metabolic activation and interferon suppression. Together, these findings suggest SARS-CoV-2 has progressively evolved toward a strategy that maintains efficient upper-airway replication while minimising epithelial stress and inflammation.

systems biology↗

bioRxiv2023

Species-wide quantitative transcriptomes and proteomes reveal distinct genetic control of gene expression variation in yeast

Gene expression varies between individuals and corresponds to a key step linking genotypes to phenotypes. However, our knowledge regarding the species-wide genetic control of protein abundance, including its dependency on transcript levels, is very limited. Here, we have determined quantitative proteomes of a large population of 942 diverse natural Saccharomyces cerevisiae yeast isolates. We found that mRNA and protein abundances are weakly correlated at the population gene level. While the protein co-expression network recapitulates major biological functions, differential expression patterns reveal proteomic signatures related to specific populations. Comprehensive genetic association analyses highlight that genetic variants associated with variation in protein (pQTL) and transcript (eQTL) levels poorly overlap (3.6%). Our results demonstrate that transcriptome and proteome are governed by distinct genetic bases, likely explained by protein turnover. It also highlights the importance of integrating these different levels of gene expression to better understand the genotype-phenotype relationship. HighlightsO_LIAt the level of individual genes, the abundance of transcripts and proteins is weakly correlated within a species ({rho} = 0.165). C_LIO_LIWhile the proteome is not imprinted by population structure, co-expression patterns recapitulate the cellular functional landscape C_LIO_LIWild populations exhibit a higher abundance of respiration-related proteins compared to domesticated populations C_LIO_LILoci that influence protein abundance differ from those that impact transcript levels, likely because of protein turnover C_LI

systems biology↗

bioRxiv2020

Amino acids whose intracellular levels change most during aging alter chronological lifespan of fission yeast

Amino acid deprivation or supplementation can affect cellular and organismal lifespan, but we know little about the role of concentration changes in free, intracellular amino acids during aging. Here, we determine free amino-acid levels during chronological aging of non-dividing fission yeast cells. We compare wild-type with long-lived mutant cells that lack the Pka1 protein of the protein kinase A signalling pathway. In wild-type cells, total amino-acid levels decrease during aging, but much less so in pka1 mutants. Two amino acids strongly change as a function of age: glutamine decreases, especially in wild-type cells, while aspartate increases, especially in pka1 mutants. Supplementation of glutamine is sufficient to extend the chronological lifespan of wild-type but not of pka1{Delta} cells. Supplementation of aspartate, on the other hand, shortens the lifespan of pka1{Delta} but not of wild-type cells. Our results raise the possibility that certain amino acids are biomarkers of aging, and their concentrations during aging can promote or limit cellular lifespan.

physiology↗

bioRxiv2020

Ribosome profiling reveals ribosome stalling on tryptophan codons upon oxidative stress in fission yeast

Modulation of translation is an essential response to stress conditions. We have investigated the translational programmes launched by the fission yeast Schizosaccharomyces pombe subject to five environmental stresses: oxidative stress, heavy metal, heat shock, osmotic shock and DNA damage. We also explored the contribution of two major defence pathways to these programmes: The Integrated Stress Response, which directly regulates translation initiation, and the stress-response MAPK pathway. To obtain a genome-wide and high-resolution view of this phenomenon, we performed ribosome profiling of control cells and of cells subject to each of the five stresses mentioned above, both in wild type background and in cells in which the Integrated Stress Response or the MAPK pathway were inactivated. Translational changes were partially dependent on the integrity of both signalling pathways. Interestingly, we found that the transcription factor Fil1, a functional homologue of the Gcn4 and Atf4 proteins (from budding yeast and mammals, respectively), was highly upregulated in most stresses. Consistent with this result, Fil1 was required for the normal response to most stresses. A large group of mRNAs were translationally downregulated, including many required for ribosome biogenesis. Overall, our data suggest that severe stresses lead to the implementation of a universal translational response, which includes energy-saving measures (reduction of ribosome production) and induction of a Fil1-mediated transcriptional programme. Surprisingly, ribosomes stalled on tryptophan codons specifically upon oxidative stress, a phenomenon that is likely caused by a decrease in charged tRNA-Tryptophan. Tryptophan stalling led to a mild translation elongation reduction and contributed to the inhibition of initiation by the Integrated Stress Response. Taken together, our results show that different stresses elicit common and specific translational responses, revealing a special and so far unknown role in Tryptophan-tRNA availability.

molecular biology↗

bioRxiv2019

A natural variant of the sole pyruvate kinase of fission yeast lowers glycolytic flux triggering increased respiration and oxidative-stress resistance but decreased growth

Cells balance glycolysis with respiration to support their energetic and biosynthetic needs in different environmental or physiological contexts. With abundant glucose, many cells prefer to grow by aerobic glycolysis, or fermentation in yeast. Using 161 natural isolates of fission yeast, we investigated the genetic basis and phenotypic effects of the fermentation-respiration balance. The laboratory and a few other strains were more dependent on respiration. This trait was associated with a missense variant in a highly conserved region of Pyk1. Pyk1 is the single pyruvate kinase in fission yeast, while most organisms possess isoforms with different activity. This variant reduced Pyk1 activity and glycolytic flux. Replacing the low-activity pyk1 allele in the laboratory strain with the common high-activity allele was sufficient to increase fermentation and decrease respiration. This metabolic reprogramming triggered systems-level adaptations in the transcriptome and proteome, and in cellular phenotypes, including increased growth and chronological lifespan, but decreased resistance to oxidative stress. Thus, low Pyk1 activity provided no growth advantage but stress tolerance, despite increased respiration. The genetic tuning of glycolytic flux by a single-nucleotide change might reflect an adaptive trade-off in a species lacking pyruvate-kinase isoforms.

genetics↗