Biology subjects

DeBerardinis, R.

Publications and source records attributed to DeBerardinis, R..

3 recordsLinked to original sources

bioRxiv2026

Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.

BackgroundCardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits -ketoglutarate dehydrogenase (-KGDH) and is associated with reduced cardiac contractile function. MethodsWe combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress. ResultsWe uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of -KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation. ConclusionOur results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.

systems biology↗

bioRxiv2020

Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism

Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutants display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC complexes appears to be independent of protein lipoylation, the best characterized function of mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. Together, these data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels.

biochemistry↗

bioRxiv2019

N-Acetyl Cysteine Abrogates Silver-Induced Reactive Oxygen Species in Human Cells Without Altering Silver-Based Antimicrobial Activity

Silver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial (16HBE) cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to restoration of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver-exposed cells. As a result of the normalized citric acid cycle, cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate (ATP) levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver.\n\nImportanceAlthough silver is a potent, broad-spectrum antibiotic, silver-induced toxicity, primarily due to generation of ROS, remains a concern limiting its use beyond treatment of wounds. NAC has been widely used as an antioxidant to rescue eukaryotic cells from metal-associated toxicity. Thus, we have evaluated the capacity of NAC to abrogate silver toxicity in a human bronchial epithelial cell line (16HBE) as a step towards expanding the use of silver-based antimicrobials to treat lung infections. We found that NAC pre-incubation resurrects a healthy metabolic state in bronchial epithelial cells exposed to silver ions via a combination of its antioxidant and metal-binding properties. Finally, this ability of NAC to rescue silver-exposed eukaryotic cells does not alter the antimicrobial activity of silver. Thus, a silver-NAC combination holds tremendous potential as a future, non-toxic antimicrobial agent.

pharmacology and toxicology↗