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dc.contributor.authorPurhonen, Janne
dc.contributor.authorGrigorjev, Vladislav
dc.contributor.authorEkiert, Robert
dc.contributor.authorAho, Noora
dc.contributor.authorRajendran, Jayasimman
dc.contributor.authorPietras, Rafał
dc.contributor.authorTruvé, Katarina
dc.contributor.authorWikström, Mårten
dc.contributor.authorSharma, Vivek
dc.contributor.authorOsyczka, Artur
dc.contributor.authorFellman, Vineta
dc.contributor.authorKallijärvi, Jukka
dc.date.accessioned2020-01-20T13:43:54Z
dc.date.available2020-01-20T13:43:54Z
dc.date.issued2020
dc.identifier.citationPurhonen, J., Grigorjev, V., Ekiert, R., Aho, N., Rajendran, J., Pietras, R., Truvé, K., Wikström, M., Sharma, V., Osyczka, A., Fellman, V., & Kallijärvi, J. (2020). A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. <i>Nature Communications</i>, <i>11</i>, Article 322. <a href="https://doi.org/10.1038/s41467-019-14201-2" target="_blank">https://doi.org/10.1038/s41467-019-14201-2</a>
dc.identifier.otherCONVID_34183360
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/67414
dc.description.abstractWe previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.D254N), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1lp.S78G tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc1 complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of mitochondrial disease phenotypes.en
dc.format.mimetypeapplication/pdf
dc.languageeng
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofseriesNature Communications
dc.rightsCC BY 4.0
dc.subject.otherenergy metabolism
dc.subject.otherepistasis
dc.subject.othermetabolic disorders
dc.titleA spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-202001201353
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Chemistryen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.description.reviewstatuspeerReviewed
dc.relation.issn2041-1723
dc.relation.volume11
dc.type.versionpublishedVersion
dc.rights.copyright© 2020 the Author(s)
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber311031
dc.subject.ysomitokondriotaudit
dc.subject.ysokoe-eläinmallit
dc.subject.ysohenkiinjääminen
dc.subject.ysomitokondrio-DNA
dc.subject.ysoaineenvaihduntahäiriöt
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p20681
jyx.subject.urihttp://www.yso.fi/onto/yso/p28104
jyx.subject.urihttp://www.yso.fi/onto/yso/p14692
jyx.subject.urihttp://www.yso.fi/onto/yso/p20961
jyx.subject.urihttp://www.yso.fi/onto/yso/p6239
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.1038/s41467-019-14201-2
dc.relation.funderSuomen Akatemiafi
dc.relation.funderAcademy of Finlanden
jyx.fundingprogramAkatemiahanke, SAfi
jyx.fundingprogramAcademy Project, AoFen
jyx.fundinginformationThis study was supported by grants from Academy of Finland (grant 259296 to V.F., grant 294652 to V.S., grant 311031 to N.A.), Swedish Research Council (grant 521-2011-3877 to V.F.), Finnish Physicians’ Society (to V.F.), Foundation for Pediatric Research in Finland (to V.F.), Folkhälsan Research Center (to V.F. and J.K.), Magnus Ehrnrooth Foundation (to V.F. and V.S.), University of Helsinki (to V.S.), Sigrid Jusélius Foundation (to V.S.), and National Science Centre, Poland (Maestro grant 2015/18/A/NZ1/00046 to A.O.).


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