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MPV17 mutations are associated with a quiescent energetic metabolic profile

2021Artigo científico Acesso aberto
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dc.contributor.authorJacinto, Sandra
dc.contributor.authorGuerreiro, Patrícia
dc.contributor.authorde Oliveira, Rita Machado
dc.contributor.authorCunha-Oliveira, Teresa
dc.contributor.authorSantos, Maria João
dc.contributor.authorGrazina, Manuela
dc.contributor.authorRego, Ana Cristina
dc.contributor.authorOuteiro, Tiago
dc.date.accessioned2021-11-30T15:33:20Z
dc.date.available2021-11-30T15:33:20Z
dc.date.issued2021
dc.description© 2021 Jacinto, Guerreiro, de Oliveira, Cunha-Oliveira, Santos, Grazina, Rego and Outeiro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.pt_PT
dc.description.abstractMutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease in vitro. We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.pt_PT
dc.description.sponsorshipSJ was funded by Fundação Calouste Gulbenkian. TO was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2067/1- 390729940). AR and TC-O were funded by Fundação para a Ciência e a Tecnologia and European Regional Development Fund (CENTRO-01-0145-FEDER-000012- HealthyAging2020), (POCI-010145-FEDER-007440), and (POCI-01-145-FEDER-29297). MS and MG were funded by UID/NEU/04539/2019 (Strategic Plan CNC.IBILI).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Cell Neurosci. 2021 Mar 17;15:641264pt_PT
dc.identifier.doi10.3389/fncel.2021.641264pt_PT
dc.identifier.eissn1662-5102
dc.identifier.urihttp://hdl.handle.net/10451/50228
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationCENTRO-01-0145-FEDER-000012pt_PT
dc.relationPOCI-010145-FEDER-007440pt_PT
dc.relationPOCI-01-145-FEDER-29297pt_PT
dc.relationCNC. IBILI
dc.relation.publisherversionhttps://www.frontiersin.org/journals/cellular-neuroscience#pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMpv17 mutationspt_PT
dc.subjectMitochondrial depletion syndromept_PT
dc.subjectMitochondrial dysfunctionpt_PT
dc.subjectNeurode generationpt_PT
dc.subjectProtein mislocationpt_PT
dc.titleMPV17 mutations are associated with a quiescent energetic metabolic profilept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberUID/NEU/04539/2019
oaire.awardTitleCNC. IBILI
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FNEU%2F04539%2F2019/PT
oaire.citation.titleFrontiers in Cellular Neurosciencept_PT
oaire.citation.volume15pt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameJacinto
person.familyNameOuteiro
person.givenNameSandra
person.givenNameTiago
person.identifier.ciencia-id8513-6FA3-63C7
person.identifier.ciencia-idBC14-20AB-8D68
person.identifier.orcid0000-0002-2798-2548
person.identifier.orcid0000-0003-1679-1727
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicatione6b6ce9e-7a29-44fb-9209-bb31f8ee6f63
relation.isAuthorOfPublicationaf7b2e31-d9da-4e83-a8f1-702910f80a40
relation.isAuthorOfPublication.latestForDiscoverye6b6ce9e-7a29-44fb-9209-bb31f8ee6f63
relation.isProjectOfPublication43c8f2c5-fade-4881-b61b-bb4503374eae
relation.isProjectOfPublication.latestForDiscovery43c8f2c5-fade-4881-b61b-bb4503374eae

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