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Cited by 16DNA Repair MechanismsRedox biology and oxidative stressAntioxidant Activity and Oxidative Stress

4-Hydroxy-2-nonenal attenuates 8-oxoguanine DNA glycosylase 1 activity

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Pan, Guodong, Deshpande, Mandar, Pang, Haiyan, Stemmer, Paul M., Carruthers, Nicholas J., Shearn, Colin T., Backos, Donald S., Palaniyandi, Suresh S.·2020·Journal of Cellular Biochemistry
DOI 10.1002/jcb.29814PMC PMC7935017
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Abstract

Elevated cellular oxidative stress and oxidative DNA damage are key contributors to impaired cardiac function in diabetes. During chronic inflammation, reactive oxygen species (ROS)‐induced lipid peroxidation results in the formation of reactive aldehydes, foremost of which is 4‐hydroxy‐2‐nonenal (4HNE). 4HNE forms covalent adducts with proteins, negatively impacting cellular protein function. During conditions of elevated oxidative stress, oxidative DNA damage such as modification by 8‐hydroxydeoxyguanosine (8OHdG) is repaired by 8‐oxoguanine glycosylase‐1 (OGG‐1). Based on these facts, we hypothesized that 4HNE forms adducts with OGG‐1 inhibiting its activity, and thus, increases the levels of 8OHG in diabetic heart tissues. To test our hypothesis, we evaluated OGG‐1 activity, 8OHG and 4HNE in the hearts of leptin receptor deficient db/db mice, a type‐2 diabetic model. We also treated the recombinant OGG‐1 with 4HNE to measure direct adduction. We found decreased OGG‐1 activity (P > .05), increased 8OHG (P > .05) and increased 4HNE adducts (P > .05) along with low aldehyde dehydrogenase‐2 activity (P > .05). The increased colocalization of OGG‐1 and 4HNE in cardiomyocytes suggest 4HNE adduction on OGG‐1. Furthermore, colocalization of 8OHG and OGG‐1 with mitochondrial markers TOM 20 and aconitase, respectively, indicated significant levels of oxidatively‐induced mtDNA damage and implicated a role for mitochondrial OGG‐1 function. In vitro exposure of recombinant OGG‐1 (rOGG‐1) with increasing concentrations of 4HNE resulted in a concentration‐dependent decrease in OGG‐1 activity. Mass spectral analysis of trypsin digests of 4HNE‐treated rOGG‐1 identified 4HNE adducts on C28, C75, C163, H179, H237, C241, K249, H270, and H282. In silico molecular modeling of 4HNE‐K249 OGG‐1 and 4HNE‐H270 OGG‐1 mechanistically supported 4HNE‐mediated enzymatic inhibition of OGG‐1. In conclusion, these data support the hypothesis that inhibition of OGG‐1 by direct modification by 4HNE contributes to decreased OGG‐1 activity and increased 8OHG‐modified DNA that are present in the diabetic heart.

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  • 4-HNE decreases activity of OGG-1, resulting in increased levels of 8-hydroxydeoxyguanosine in DNA.

    “Finally, 4-HNE has also been found to decrease the activity of the DNA repair enzyme 8-oxoguanine glycosylase-1 (OGG-1), possibly due to covalent alkylation of the protein, resulting in increased levels 8-hydroxydeoxyguanosine in the DNA [83].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [83]

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Cited by

Sorted by citations

Authors
Pan, G., Deshpande, M., Pang, H., Stemmer, P. M., Carruthers, N. J., Shearn, C. T., Backos, D. S., & Palaniyandi, S. S.
Affiliations
  • Henry Ford Health (US)
  • Wayne State University (US)
  • University of Colorado Anschutz (US)
Corresponding author
Palaniyandi, Suresh S.
ORCID
Venue
Journal of Cellular Biochemistry
Publisher
Wiley
Published
2020-07-06
Volume
121
Issue
12
Pages
4887-4897
ISSN
  • 0730-2312 (ISSN-L)
  • 1097-4644
DOI
10.1002/jcb.29814
PMC
PMC7935017
OpenAlex
W3040579620
Cited by
16
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 2
FWCI
0.88
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Cellular Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (1R01HL139877‐01A1, 1R56 HL131891‐01A1)
  • Henry Ford Health System (A10249)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords
4-hydroxynonenal, OGG1, oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, lipid peroxidation, protein aldehyde adducts, ALDH2, diabetic cardiomyopathy, type 2 diabetes, db/db mice, mitochondrial DNA damage, cardiomyocytes

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