Song 2018 Proc Natl Acad Sci U S A

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Song E, Ramos SV, Huang X, Liu Y, Botta A, Sung HK, Turnbull PC, Wheeler MB, Berger T, Wilson DJ, Perry CGR, Mak TW, Sweeney G (2018) Holo-lipocalin-2-derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes. Proc Natl Acad Sci U S A 115:1576-81.

» PMID: 29378951 Open Access

Song E, Ramos SV, Huang X, Liu Y, Botta A, Sung HK, Turnbull PC, Wheeler MB, Berger T, Wilson DJ, Perry CGR, Mak TW, Sweeney G (2018) Proc Natl Acad Sci U S A

Abstract: Lipocalin-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.

Keywords: NGAL, Iron, Lipocalin-2, Reactive oxygen species, Siderophore Bioblast editor: Kandolf G O2k-Network Lab: CA Toronto Perry CG


Labels: MiParea: Respiration, Genetic knockout;overexpression 


Organism: Rat  Tissue;cell: Heart  Preparation: Intact cells 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k 

Labels, 2018-03