Biology subjects

Giese, G. E.

Publications and source records attributed to Giese, G. E..

4 recordsLinked to original sources

bioRxiv2022

D-2-Hydroxyglutarate dehydrogenase connects the propionate shunt to ketone body metabolism in Caenorhabditis elegans

In humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Deletion of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the upregulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG, or by supplementing either vitamin B12 or the ketone body 3-hydroxybutyrate (3HB). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low, and in which a loss of dhgd-1 causes lethality by limiting ketone body production. HIGHLIGHTS- D-2-hydroxyglutarate is produced by HPHD-1 in the propionate shunt pathway - DHGD-1 recycles 2-hydroxyglutarate to sustain flux through the propionate shunt - dhgd-1 loss perturbs ketone body metabolism and causes embryonic lethality - 3-Hydroxybutyrate, vitamin B12 or hphd-1 RNAi rescue dhgd-1 mutant lethality

biochemistry↗

bioRxiv2020

WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization

In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology and the response to therapeutic drugs. On March 15, 2020, a stay-at-home order was put into effect in the state of Massachusetts, USA, to flatten the curve of the spread of the novel SARS-CoV2 virus that causes COVID-19. For biomedical researchers in our state, this meant putting a hold on experiments for nine weeks until May 18, 2020. To keep the lab engaged and productive, and to enhance communication and collaboration, we embarked on an in-lab project that we all found important but that we never had the time for: the detailed annotation and drawing of C. elegans metabolic pathways. As a result, we present WormPaths, which is composed of two parts: 1) the careful manual annotation of metabolic genes into pathways, categories and levels, and 2) 66 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on our WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the unfortunate event of additional lockdowns, we envision further developing these maps to be more interactive, with an analogy of road maps that are available on mobile devices.

genetics↗

bioRxiv2018

A Persistence Detector for Metabolic Network Rewiring in an Animal

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental signals. Gene regulatory network circuitries known as coherent type 1 feed-forward loops (FFLs) with AND-logic gates have been proposed to function as a persistence detector because it generates a delay in target activation and prevents target induction unless the input signal is sustained. While such a circuit has been found for the L-arabinose utilization system in E. coli, their existence and relevance multicellular organisms has remained unclear. Here, we identify the first persistence detector in an animal that redirects propionate breakdown to a shunt pathway when flux through the canonical propionate breakdown pathway is perturbed. We propose that this mechanism has evolved to ensure the shunt pathway stays off unless propionate accumulation is persistent because the shunt pathway generates highly toxic acrylate. Our study uniquely connects persistence detector circuitry to a physiological response in an animal.

systems biology↗

bioRxiv2017

C. elegans Multidrug Resistance Protein 5 (MRP-5) Transports Vitamin B12 from the Intestine to the Gonad to Support Embryonic Development

Vitamin B12 functions as a cofactor for methionine synthase to produce the anabolic methyl donor S-adenosylmethionine (SAM) and for methylmalonyl-CoA mutase to catabolize the short chain fatty acid propionate. In the nematode Caenorhabditis elegans, maternally supplied vitamin B12 is required for the development of her offspring. However, the mechanism for exporting vitamin B12 from the mother to her offspring is not yet known. Here, we use RNAi of more than 200 transporters with a vitamin B12-sensor transgene to identify the ABC transporter MRP-5 as a candidate vitamin B12 exporter. We show that injection of vitamin B12 into the gonad of mrp-5 deficient mothers rescues embryonic lethality in her offspring. Altogether, our findings identify a maternal mechanism for the transit of an essential vitamin to support the development of the next generation.

developmental biology↗