4-Hydroxy-7-oxo-5-heptenoic acid lactone can induce mitochondrial dysfunction in retinal pigmented epithelial cells.

Autor: Cheng YS; Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA., Linetsky M; Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA., Li H; Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA., Ayyash N; Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA., Gardella A; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA., Salomon RG; Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA. Electronic address: rgs@case.edu.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2020 Nov 20; Vol. 160, pp. 719-733. Date of Electronic Publication: 2020 Sep 10.
DOI: 10.1016/j.freeradbiomed.2020.09.009
Abstrakt: Oxidation of docosahexaenoate (DHA)-containing phospholipids in the cell plasma membrane leads to release of the α,β-unsaturated aldehyde 4-hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone which is capable of inducing retinal pigmented epithelial (RPE) cell dysfunction. Previously, HOHA lactone was shown to induce apoptosis and angiogenesis, and to activate the alternative complement pathway. RPE cells metabolize HOHA lactone through enzymatic conjugation with glutathione (GSH). Competing with this process is the adduction of HOHA lactone to protein lysyl residues generating 2-(ω-carboxyethyl)pyrrole (CEP) derivatives that have pathological relevance to age-related macular degeneration (AMD). We now find that HOHA lactone induces mitochondrial dysfunction. It decreases ATP levels, mitochondrial membrane potentials, enzymatic activities of mitochondrial complexes, depletes GSH and induces oxidative stress in RPE cells. The present study confirmed that pyridoxamine and other primary amines, which have been shown to scavenge γ-ketoaldehydes formed by carbohydrate or lipid peroxidation, are ineffective for scavenging the α,β-unsaturated aldehydes. Histidyl hydrazide (HH), that has both hydrazide and imidazole nucleophile functionalities, is an effective scavenger of HOHA lactone and it protects ARPE-19 cells against HOHA lactone-induced cytotoxicity. The HH α-amino group is not essential for this electrophile trapping activity. The N α -acyl L-histidyl hydrazide derivatives with 2- to 7-carbon acyl groups with increasing lipophilicities are capable of maintaining the effectiveness of HH in protecting ARPE-19 cells against HOHA lactone toxicity, which potentially has therapeutic utility for treatment of age related eye diseases.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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