A function for lipoxygenase in programmed organelle degradation

Leyen, Klaus van; Duvoisin, Robert M.; Engelhardt, Harald; Wiedmann, Martin

doi:10.1038/26500

Cited by 273 publications

(241 citation statements)

References 22 publications

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“…Reticulocyte culture from those knock-out animals mimicked closely the mitochondrial exclusion defect we observed in the Mutators 15,17,20 . Furthermore, pharmacological inhibition of 15-lipoxygenase (15-LOX), an enzyme involved in degradation of mitochondria during reticulocyte maturation, led to an accumulation of mitochondria in a subset of mature erythrocytes 13,36 . Nonetheless, in all of these murine models the majority of the mature erythrocytes lacked mitochondria, suggesting considerable functional redundancy in organelle clearance during erythroid development.…”

Section: Discussionmentioning

confidence: 99%

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

et al. 2015

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Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

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Section: Discussionmentioning

confidence: 99%

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

et al. 2015

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“…Indeed, LOX-1 has been shown to utilize phospholipids in lipid bilayers (41), and fatty acids inserted into phospholipid micelles (16), as physiological substrates. Such activity has received increasing interest since the discovery that lipoxygenase forms pore-like structures in biomembranes, thus leading to programmed organelle degradation (42). Nevertheless, it is still unclear how this membrane binding is regulated, though recent evidence strongly suggests that soybean LOX-1 (43) and also human 5-lipoxygenase (44) and 15-lipoxygenase (45) bind membranes through a calcium-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Tryptic Digestion of Soybean Lipoxygenase-1 Generates a 60 kDa Fragment with Improved Activity and Membrane Binding Ability

et al. 2001

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Lipoxygenases are key enzymes in the metabolism of unsaturated fatty acids. Soybean lipoxygenase-1 (LOX-1), a paradigm for lipoxygenases isolated from different sources, is composed of two domains: a ∼30 kDa N-terminal domain and a ∼60 kDa C-terminal domain. We used limited proteolysis and gel-filtration chromatography to generate and isolate a ∼60 kDa fragment of LOX-1 ("mini-LOX"), produced by trypsin cleavage between lysine 277 and serine 278. Mini-LOX was subjected to N-terminal sequencing and to electrophoretic, chromatographic, and spectroscopic analysis. Mini-LOX was found to be more acidic and more hydrophobic than LOX-1, and with a higher content of R-helix. Kinetic analysis showed that mini-LOX dioxygenates linoleic acid with a catalytic efficiency approximately 3-fold higher than that of LOX-1 (33.3 × 10 6 and 10.9 × 10 6 M -1 ‚s -1 , respectively), the activation energy of the reaction being 4.5 ( 0.5 and 8.3 ( 0.9 kJ‚mol -1 for mini-LOX and LOX-1, respectively. Substrate preference, tested with linoleic, R-linolenic, and arachidonic acids, and with linoleate methyl ester, was the same for LOX-1 and mini-LOX, and also identical was the regio-and stereospecificity of the products generated thereof, analyzed by reversed-phase and chiral high-performance liquid chromatography, and by gas chromatography/mass spectrometry. Mini-LOX was able to bind artificial vesicles with higher affinity than LOX-1, but the binding was less affected by calcium ions than was that of LOX-1. Taken together, these results suggest that the N-terminal domain of soybean lipoxygenase-1 might be a built-in inihibitor of catalytic activity and membrane binding ability of the enzyme, with a possible role in physio-(patho)logical conditions.Lipoxygenases are a family of monomeric non-heme, nonsulfur iron dioxygenases which catalyze the conversion of unsaturated fatty acids into conjugated hydroperoxides. Mammalian lipoxygenases have been implicated in the pathogenesis of several inflammatory conditions such as arthritis, psoriasis, and bronchial asthma (1). They have been also implicated in atherosclerosis (2), brain aging (3), HIV infection (4), and kidney disease (5, 6). In plants, lipoxygenases favor germination and participate in the synthesis of traumatin and jasmonic acid and in the response to abiotic stress (7). Recently, they have been also shown to initiate the programmed death (apoptosis) of plant cells (8). Soybean lipoxygenase-1 (LOX-1) 1 is widely used as a prototype for studying the homologous family of lipoxygenases from tissues of different species, both in structural (9-13) and in kinetic (14-18) investigations. The amino acid sequence (19) and three-dimensional structure (9, 10) of LOX-1 have been determined. The overall 839 amino acid residues of LOX-1, with a molecular mass of 93 840 Da, show 2 domains. The first 146 N-terminal amino acid residues form an 8-stranded -barrel, and the remaining 693 residues of the C-terminal domain are organized into 23 helices and 8 -strands. Mammalian lipoxygenases do ...

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“…Lipid peroxidation by LOXs can also cause permeabilization of organelle and plasma membranes. 13 As oxidative rancidity is mediated by increased LOX activity, the LOX-inhibiting activity of BHA may contribute to its action as a food preservative. To determine whether the LOX-inhibiting activity affects cell death, we compared the influence of two LOX inhibitors, nordihydroguaiaretic acid (NDGA, a general LOX inhibitor) and AA861 (a 5-LOX specific inhibitor), with the effect of BHA.…”

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confidence: 99%