Biology subjects

Mosegaard, S.

Publications and source records attributed to Mosegaard, S..

3 recordsLinked to original sources

bioRxiv2025

Integrated Multi-Omics Mapping of Mitochondrial Dysfunction and Substrate Preference in Barth Syndrome Cardiac Tissue

Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. With this study describe a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.

molecular biology↗

bioRxiv2023

Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in the activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for the subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of the tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1{beta}. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn fatty acid oxidation disorders, we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from normal healthy controls by targeted loss-of-function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. With this report, we therefore provide genetic evidence from two genetically distinct but phenotypically similar human metabolic diseases, that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to LPS.

immunology↗

bioRxiv2023

Tracer-based lipidomics identifies novel disease-specific biomarkers in mitochondrial β-oxidation disorders

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and possible influence on cellular lipid homeostasis are, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore new disease markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two new candidate disease markers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second biomarker is an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. These are hypothesized to be degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two new disease markers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.

molecular biology↗