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Article: Holo-lipocalin-2–derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes

TitleHolo-lipocalin-2–derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes
Authors
KeywordsNGAL
Siderophore
Iron
Reactive oxygen species
Lipocalin-2
Issue Date2018
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2018, v. 115, n. 7, p. 1576-1581 How to Cite?
AbstractLipocalin-2 (Lcn2), a critical component of the innate immune response which binds siderophores and limits bacterial iron acquisition, can elicit spillover adverse proinflammatory effects. Here we show that holo-Lcn2 (Lcn2–siderophore–iron, 1:3:1) increases mitochondrial reactive oxygen species (ROS) generation and attenuates mitochondrial oxidative phosphorylation in adult rat primary cardiomyocytes in a manner blocked by N-acetyl-cysteine or the mitochondria-specific antioxidant SkQ1. We further demonstrate using siderophores 2,3-DHBA (2,3-dihydroxybenzoic acid) and 2,5-DHBA that increased ROS and reduction in oxidative phosphorylation are direct effects of the siderophore component of holo-Lcn2 and not due to apo-Lcn2 alone. Extracellular apo-Lcn2 enhanced the potency of 2,3-DHBA and 2,5-DHBA to increase ROS production and decrease mitochondrial respiratory capacity, whereas intracellular apo-Lcn2 attenuated these effects. These actions of holo-Lcn2 required an intact plasma membrane and were decreased by inhibition of endocytosis. The hearts, but not serum, of Lcn2 knockout (LKO) mice contained lower levels of 2,5-DHBA compared with wild-type hearts. Furthermore, LKO mice were protected from ischemia/ reperfusion-induced cardiac mitochondrial dysfunction. Our study identifies the siderophore moiety of holo-Lcn2 as a regulator of cardiomyocyte mitochondrial bioenergetics.
Persistent Identifierhttp://hdl.handle.net/10722/293069
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSong, Erfei-
dc.contributor.authorRamos, Sofhia V.-
dc.contributor.authorHuang, Xiaojing-
dc.contributor.authorLiu, Ying-
dc.contributor.authorBotta, Amy-
dc.contributor.authorSung, Hye Kyoung-
dc.contributor.authorTurnbull, Patrick C.-
dc.contributor.authorWheeler, Michael B.-
dc.contributor.authorBerger, Thorsten-
dc.contributor.authorWilson, Derek J.-
dc.contributor.authorPerry, Christopher G.R.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorSweeney, Gary-
dc.date.accessioned2020-11-17T14:57:48Z-
dc.date.available2020-11-17T14:57:48Z-
dc.date.issued2018-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2018, v. 115, n. 7, p. 1576-1581-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/293069-
dc.description.abstractLipocalin-2 (Lcn2), a critical component of the innate immune response which binds siderophores and limits bacterial iron acquisition, can elicit spillover adverse proinflammatory effects. Here we show that holo-Lcn2 (Lcn2–siderophore–iron, 1:3:1) increases mitochondrial reactive oxygen species (ROS) generation and attenuates mitochondrial oxidative phosphorylation in adult rat primary cardiomyocytes in a manner blocked by N-acetyl-cysteine or the mitochondria-specific antioxidant SkQ1. We further demonstrate using siderophores 2,3-DHBA (2,3-dihydroxybenzoic acid) and 2,5-DHBA that increased ROS and reduction in oxidative phosphorylation are direct effects of the siderophore component of holo-Lcn2 and not due to apo-Lcn2 alone. Extracellular apo-Lcn2 enhanced the potency of 2,3-DHBA and 2,5-DHBA to increase ROS production and decrease mitochondrial respiratory capacity, whereas intracellular apo-Lcn2 attenuated these effects. These actions of holo-Lcn2 required an intact plasma membrane and were decreased by inhibition of endocytosis. The hearts, but not serum, of Lcn2 knockout (LKO) mice contained lower levels of 2,5-DHBA compared with wild-type hearts. Furthermore, LKO mice were protected from ischemia/ reperfusion-induced cardiac mitochondrial dysfunction. Our study identifies the siderophore moiety of holo-Lcn2 as a regulator of cardiomyocyte mitochondrial bioenergetics.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectNGAL-
dc.subjectSiderophore-
dc.subjectIron-
dc.subjectReactive oxygen species-
dc.subjectLipocalin-2-
dc.titleHolo-lipocalin-2–derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1720570115-
dc.identifier.pmid29378951-
dc.identifier.pmcidPMC5816208-
dc.identifier.scopuseid_2-s2.0-85042015846-
dc.identifier.volume115-
dc.identifier.issue7-
dc.identifier.spage1576-
dc.identifier.epage1581-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000424876000079-
dc.identifier.issnl0027-8424-

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