Biology subjects

Koecher, T.

Publications and source records attributed to Koecher, T..

3 recordsLinked to original sources

bioRxiv2021

A genetic program boosts mitochondrial function to power macrophage tissue invasion

Metabolic adaptation to changing demands underlies homeostasis. During inflammation or metastasis, cells leading migration into challenging environments require an energy boost, however what controls this capacity is unknown. We identify a previously unstudied nuclear protein, Atossa, as changing metabolism in Drosophila melanogaster immune cells to promote tissue invasion. Atossas vertebrate orthologs, FAM214A-B, can fully substitute for Atossa, indicating functional conservation from flies to mammals. Atossa increases mRNA levels of Porthos, an unstudied RNA helicase and two metabolic enzymes, LKR/SDH and GR/HPR. Porthos increases translation of a gene subset, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Respiration measurements and metabolomics indicate that Atossa and Porthos powers up mitochondrial oxidative phosphorylation to produce sufficient energy for leading macrophages to forge a path into tissues. As increasing oxidative phosphorylation enables many crucial physiological responses, this unique genetic program may modulate a wide range of cellular behaviors beyond migration.

cell biology↗

bioRxiv2021

Revisiting a GWAS peak in Arabidopsis thaliana reveals possible confounding by genetic heterogeneity

Genome-wide association studies (GWAS) have become a standard approach for exploring the genetic basis of phenotypic variation. However, correlation is not causation, and only a tiny fraction of all associations have been experimentally confirmed. One practical problem is that a peak of association does not always pinpoint a causal gene, but may instead be tagging multiple causal variants. In this study, we reanalyze a previously reported peak associated with flowering time traits in Swedish in Arabidopsis thaliana. The peak appeared to pinpoint the AOP2/AOP3 cluster of glucosinolate biosynthesis genes, which is known to be responsible for natural variation in herbivore resistance. Here we propose an alternative hypothesis, by demonstrating that the AOP2/AOP3 flowering association can be wholly accounted for by allelic variation in two flanking genes with clear roles in regulating flowering: NDX1, a regulator of the main flowering time controller FLC, and GA1, which plays a central role in gibberellin synthesis and is required for flowering under some conditions. In other words, we propose that the AOP2/AOP3 flowering-time association is yet another example of a spurious, "synthetic" association, arising from trying to fit a single-locus model in the presence of two statistically associated causative loci.

genetics↗

bioRxiv2020

Benchmarking non-targeted metabolomics using yeast derived libraries

Non-targeted analysis by high-resolution mass spectrometry (HRMS) is the essential discovery tool in metabolomics. Up to date, standardization and validation remain a challenge. Community wide accepted, cost-effective benchmark materials are lacking. In this work, we propose yeast (Pichia pastoris) extracts, derived from fully controlled fermentations for this purpose. We established an open-source metabolite library of > 200 metabolites, reproducibly recovered in ethanolic extracts by orthogonal LCHRMS methods, different fermentations (over three years) and different laboratories. More specifically, compound identification was based on accurate mass, matching retention times, and MS/MS spectra as compared to authentic standards and internal databases. The library includes metabolites from the classes of 1) organic acids and derivatives (2) nucleosides, nucleotides and analogues, (3) lipids and lipid-like molecules, (4) organic oxygen compounds, (5) organoheterocyclic compounds, (6) organic nitrogen compounds and (7) benzoids at expected concentrations ranges of sub-nM to {micro}M. As yeast is a eukaryotic organism, key regulatory elements are highly conserved between yeast and all annotated metabolites were also reported in the Human metabolome data base (HMDB). A large fraction of metabolites was found to be stable for several years when stored at -80{degrees}C. Thus, the yeast benchmark material enabled not only to test for the chemical space and coverage upon method implementation and developments, but enabled in-house routines for instrumental performance tests. Finally, the benchmark material opens new avenues for batch to batch corrections in large scale non-targeted metabolomics studies.

biochemistry↗