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Hub Molecules Of Life

Description: Popular science description: The previously established workflow among all partners has been further consolidated during the present project period. Besides regular online meetings, all partners have met in person end of September 2025 in Tromsø in conjunction with a Marie Skladowska Curie Action that three of the four partners are part of. In our scientific activities, we have made a critical step forward in the time-resolved quantification of protein acetylation. This will now enable us to map out global and site-specific acetylation dynamics and the dependence on global and compartment-specific NAD and CoA concentrations. We have also extended the method development to include two other important coenzymes (flavin adenine dinucleotide, FAD, and S-adenosylmethionine, SAM), in addition to NAD and CoA, into our analytical pipelines. Moreover, in initial experiments, we have been able to detect and quantify global protein methylation in human cells. Thereby, we have made an important step towards quantifying and modulating protein methylation dynamics in human cells. A major effort was directed towards understanding the interconnectivity of subcellular NAD pools. Using genetic engineering, high-resolution mass spectrometry and fluxomics as well as advanced imaging techniques, we could establish a new role of mitochondria in coordinating and buffering subcellular NAD fluctuations. This newly discovered function of these organelles has important implications for intracellular (intercompartmental) communication and regulation of metabolic and NAD-dependent signaling pathways. Mechanistically, the NAD rheostat function is based on the mitochondrial NAD transporter SLC25A51 and the reversibility of the mitochondrial NMN adenylyltransferase isoform (NMNAT3). The identification of this mechanism was greatly facilitated by the development and in-depth characterization of cellular models of chronic NAD depletion, an aging-associated phenomenon in various tissues. In upcoming studies, we will analyze transcriptional alterations in these models and compare them to aging-dependent changes in gene expression. In these analyses, we will also include the prediction of metabolic alterations using GEMCAT, a genome-wide modeling tool which we have established during this project period. Project summary: Metabolic disorders are a major burden on the European population and health care systems. Moreover, metabolic perturbations contribute substantially to other pathologies such as neurodegenerative disorders and cancer. The causes of metabolic dysregulation are manifold and lead to pathological shifts in biochemical processes, often in response to imbalanced nutrition. Likewise, changes in metabolism affect signalling mechanisms and gene regulation, aggravating the pathology. The tight interconnection between metabolism and signalling is still not well understood. HubMOL will fill this knowledge gap and open new horizons by exploring the functional duality of a set of small molecules that are involved in all cellular functions - the Hub Molecules Of Life (HubMOLs) including ATP, SAM (S-adenosylmethionine) and the vitamin-derived cofactors, NAD, FAD, and CoA. They mediate both metabolic reactions, but also signalling, for example, through posttranslational protein modifications (PTMs). The complexity of this emerging area requires interdisciplinary scientists equipped with a comprehensive set of skills and competences covering synthetic and analytical chemistry, experimental, computational and systems biology as well as clinical medicine. In a highly interactive team of international experts in these areas, HubMOL will develop new chemical and analytical tools enabling experimental studies of the complex interplay of cofactor metabolism and the dynamics of the PTMs they mediate. Predictive mathematical models will be developed to capture this interconnectivity and duality of hub molecules. These models will be iteratively improved through experimental verification cycles and eventually validated based on clinical data and samples from patients with neurodegenerative disorders undergoing NAD supplementation therapy. Thereby, HubMOL will establish fundamentally new insights into cofactor biology and lay the ground for patient-tailored vitamin supplementation concepts. Teaser: The previously established workflow among all partners has been further consolidated during the present project period. Besides regular online meetings, all partners have met in person end of September 2025 in Tromsø in conjunction with a Marie Skladowska Curie Action that three of the four partn... Disciplines: [["Medisin og helsefag", "Basale medisinske, odont. og veterinærmed. fag", "Medisinsk biokjemi"]] Geographies: [["Vestland", "Bergen"]]

Funder: Norges Forskningsråd

Amount: NOK 12,500,000

Funding type: research

Funder scheme: FRIPROSJEKT-FRIPROSJEKT

Start date: 2022-01-01

End date: 2028-12-31

Investigator: Mathias Ziegler

Institution: UNIVERSITETET I BERGEN

Funded outputs count: 0

Funder award ID: rcn-foriss-325172

OpenAlex ID: G5714533423