Defining Caenorhabditis elegans as a model system to investigate lipoic acid metabolism

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dc.citation.titleJournal of Biological Chemistry (JBC)
dc.citation.volume1-14
dc.contributor.orcidhttps://orcid.org/0000-0002-1444-8661
dc.creatorLavatelli, Antonela
dc.creatorDe Mendoza, Diego
dc.creatorMansilla, María Cecilia
dc.date.accessioned2024-04-09T13:09:34Z
dc.date.available2024-04-09T13:09:34Z
dc.date.issued2021-01-04
dc.description.abstractLipoic acid (LA) is a sulfur-containing cofactor that covalently binds to a variety of cognate enzymes that are essential for redox reactions in all three domains of life. Inherited mutations in the enzymes that make LA, namely lipoyl synthase, octanoyltransferase, and amidotransferase, result in devastating human metabolic disorders. Unfortunately, because many aspects of this essential pathway are still obscure, available treatments only serve to alleviate symptoms. We envisioned that the development of an organismal model system might provide new opportunities to interrogate LA biochemistry, biology, and physiology. Here we report our investigations on three Caenorhabditis elegans orthologous proteins involved in this post-translational modification. We established that M01F1.3 is a lipoyl synthase, ZC410.7 an octanoyltransferase, and C45G3.3 an amidotransferase. Worms subjected to RNAi against M01F1.3 and ZC410.7 manifest larval arrest in the second generation. The arrest was not rescued by LA supplementation, indicating that endogenous synthesis of LA is essential for C. elegans development. Expression of the enzymes M01F1.3, ZC410.7, and C45G3.3 completely rescue bacterial or yeast mutants affected in different steps of the lipoylation pathway, indicating functional overlap. Thus, we demonstrate that, similarly to humans, C. elegans is able to synthesize LA de novo via a lipoyl-relay pathway, and suggest that this nematode could be a valuable model to dissect the role of protein mislipoylation and to develop new therapies.
dc.description.filFil: Lavatelli, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana; Argentina.
dc.description.filFil: Lavatelli, Antonela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Microbiología; Argentina.
dc.description.filFil: De Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana; Argentina.
dc.description.filFil: De Mendoza, Diego. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Microbiología; Argentina.
dc.description.filFil: Mansilla, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana; Argentina.
dc.description.filFil: Mansilla, María Cecilia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Microbiología; Argentina.
dc.description.sponsorshipAgencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (Agencia I+D+i): PICT 2014-3693
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET): P-UE 2016-IBR
dc.description.sponsorshipMinisterio de Ciencia, Tecnología e Innovación (MinCyT): EULACH 16/T02-0161
dc.description.versionpeerreviewed
dc.identifier.issn0021-9258
dc.identifier.urihttps://hdl.handle.net/2133/26859
dc.language.isoen
dc.publisherASBMB
dc.relation.publisherversionhttps://doi.org/10.1074/jbc.RA120.013760
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0021925817489058?via%3Dihub
dc.rightsopenAccess
dc.rights.holderLavatelli, Antonela
dc.rights.holderDe Mendoza, Diego
dc.rights.holderMansilla, María Cecilia
dc.rights.holderUniversidad Nacional de Rosario
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCaenorhabditis elegans
dc.subjectDevelopment
dc.subjectEnergy metabolism
dc.subjectFatty acid metabolism
dc.subjectInborn error of metabolism
dc.subjectLipoic acid
dc.subjectMitochondrial metabolism
dc.subjectOxidative stress
dc.subjectPost-translational modification
dc.subjectRNA interference
dc.titleDefining Caenorhabditis elegans as a model system to investigate lipoic acid metabolism
dc.typearticulo
dc.type.versionpublishedVersion

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