Cellular injury induced by oxidative stress is mediated through lysosomal damage
Abstract
Cultured primary hepatocytes pretreated (protected) with the iron chelator deferoxamine or the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD) were resistant to the toxicity of 5 microM naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) during a 180-min exposure. Hepatocytes exposed to naphthazarin without any protection were abruptly depleted of intracellular reduced glutathione, and the level of cytosolic Ca2+ was rapidly increased. This was followed by lipid peroxidation, measured as accumulation of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNA) intra- and extracellularly; decrease in ATP levels; destabilization of lysosomes; and finally cell death. The stability of the lysosomal membranes was evaluated by determining retention of the lysosomotropic weak base acridine orange (AO). Naphthazarin exposure caused leakage of protons from the acidic compartment, as indicated by relocalization of AO to the cytosol. Protection of the cell cultures with deferoxamine or DPPD prevented destabilization of lysosomes and cell killing. It also reduced the loss of ATP but did not prevent the depletion of glutathione or the increase in Ca2+. In cells subjected to naphthazarin exposure, DPPD protection also completely inhibited lipid peroxidation, whereas deferoxamine pretreatment only slightly reduced the intracellular accumulation of MDA and 4-HNA but completely prevented cell rupture and the leakage of these lipid peroxidation products to the medium that took place in large amounts from unprotected cells exposed to naphthazarin. Deferoxamine is taken up by endocytosis and is thus transported to the acidic vacuolar apparatus, whereas the lipophilic DPPD is rapidly distributed throughout the cells. Inhibiting endocytosis during deferoxamine pretreatment, by incubating at +4 degrees C or by preexposure to a mixture of the endocytosis-inhibitors cytochalasin B and monensin, abolished the protective effect of deferoxamine. The findings suggest that naphthazarin-induced cell killing is not caused directly by either thiol oxidation or an increase in cytosolic free Ca2+, but rather is preceded by lysosomal destabilization, which may be prevented either by inhibition of cellular peroxidation in general or by prevention of iron-catalyzed oxidative reactions, and involves peroxidation of cellular membranes, energy depletion, and leakage of lysosomal content. DPPD would protect against cell killing by preventing lipid peroxidation of cellular membranes in general, whereas deferoxamine seems to allow a limited general cellular peroxidation but specifically prevents peroxidation and fragmentation of lysosomal membranes by chelating intralysosomal iron and, consequently, leakage of destructive lysosomal contents with ensuing cell rupture and death. Thus, a certain degree of cellular peroxidation does not appear to be lethal as long as lysosomal membranes are protected, placing lysosomes into a category of cellular loci minora resistentia.
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Free iron potentiates generation of highly reactive oxygen free radicals through Fenton and Haber Weiss reactions, resulting in oxidative damage and skin photoaging.
“Through the Fenton and Haber Weiss reactions, the free iron potentiates the generation of highly reactive oxygen free radicals such as hydroxyl radical, thus resulting in oxidative damage and skin photoaging [63].”
From Boosting the Photoaged Skin: The Potential Role of Dietary Components (2021) · cites this paper as [63]
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- Authors
- Öllinger, K., & Brunk, U. T.
- Affiliations
- Linköping University (SE)
- Corresponding author
- Öllinger, Karin
- ORCID
- Öllinger, Karin
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 1995-11
- Volume
- 19
- Issue
- 5
- Pages
- 565-574
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2094148780
- Cited by
- 243
- References
- 46
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 7 · 2013: 6 · 2012: 5
- FWCI
- 16.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- naphthazarin, hepatocyte injury, lysosomal destabilization, oxidative stress, deferoxamine, DPPD, lipid peroxidation, glutathione depletion, intracellular calcium, acridine orange, endocytosis, iron-catalyzed oxidation, cell death, membrane peroxidation, ATP depletion, malondialdehyde, 4-hydroxyalkenals
- MeSH terms
- Adenosine Triphosphate, Animals, Antineoplastic Agents, Antioxidants, Calcium, Cell Survival, Cells, Cultured, Cytochalasin B, Cytosol, Deferoxamine, Endocytosis, Glutathione, Iron Chelating Agents, Kinetics, Liver, Lysosomes, Male, Monensin, Naphthoquinones, Phenylenediamines, Time Factors, Rats, Wistar, Oxidative Stress, Rats
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