Oxidative stress induces different tissue dependent effects on Mutyh-deficient mice

Jingwen Chen, Zhenqian Huang, Xin Wu, Jiaqi Kang, Yan Ren, Wei Gao, Xiang Lu, Jingmei Wang, Weidong Ding, Yusaku Nakabeppu, Yimei Fan, Yaping Wang

Research output: Contribution to journalArticle

Abstract

8-oxoguanine (8-oxoG) is one of the most prevalent genotoxic lesions, and it is generated in DNA attacked by reactive oxygen species (ROS). Adenine misincorporated opposite to 8-oxoG during replication is excised by MutY homolog (MUTYH), an important protein of the base excision repair (BER) system. Mutyh plays an important role in the maintenance of genomic integrity, but the functional consequences of Mutyh deficiency are not fully understood. In the current study, we investigated the histological and functional changes of five tissues (hippocampus, heart, liver, kidney and lung) and their molecular basis in Mutyh−/− and wild-type mice exposed to D-galactose (D-gal). Our data indicated that Mutyh deficiency hindered the weight gain of experimental mice and induced substantial alterations of 8-oxoG content and superoxide dismutase (SOD) activity, but no significant histological and functional impairment appeared in the investigated tissues of Mutyh- deficient mice without D-gal exposure. Under low-dose D-gal exposure, Mutyh deficiency altered expression of genes involved in mitochondrial unfolded protein response (UPRmt) in the heart, liver and lung, and caused an enhanced expression of mitochondrial dynamics proteins (MDPs) in hippocampus and liver. The stress responses could maintain mitochondrial proteostasis and function. However, such responses were not noted when experiencing excessive damage burden induced by high-dose D-gal exposure, in which Mutyh deficiency increased accumulation of 8-oxoG and aggravated mitonuclear protein imbalance, as well as histological lesions in heart, liver and kidney. A higher sensitivity to ROS-induced cardiotoxicity with high-dose D-gal exposure was noticed in Mutyh−/− mice. However, no differences in learning and memory impairments were observed between Mutyh−/− and wild-type mice with high-dose D-gal exposure. In conclusion, our data demonstrated that Mutyh deficiency has different impacts on various tissues based on the degree of oxidative stress.

Original languageEnglish
Pages (from-to)482-493
Number of pages12
JournalFree Radical Biology and Medicine
Volume143
DOIs
Publication statusPublished - Nov 1 2019

Fingerprint

Oxidative stress
Galactose
Oxidative Stress
Tissue
Liver
Mitochondrial Proteins
Reactive Oxygen Species
Hippocampus
Mitochondrial Dynamics
Kidney
Unfolded Protein Response
Lung
Proteins
Adenine
DNA Repair
Superoxide Dismutase
Weight Gain
Repair
Genes
Maintenance

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Oxidative stress induces different tissue dependent effects on Mutyh-deficient mice. / Chen, Jingwen; Huang, Zhenqian; Wu, Xin; Kang, Jiaqi; Ren, Yan; Gao, Wei; Lu, Xiang; Wang, Jingmei; Ding, Weidong; Nakabeppu, Yusaku; Fan, Yimei; Wang, Yaping.

In: Free Radical Biology and Medicine, Vol. 143, 01.11.2019, p. 482-493.

Research output: Contribution to journalArticle

Chen, J, Huang, Z, Wu, X, Kang, J, Ren, Y, Gao, W, Lu, X, Wang, J, Ding, W, Nakabeppu, Y, Fan, Y & Wang, Y 2019, 'Oxidative stress induces different tissue dependent effects on Mutyh-deficient mice', Free Radical Biology and Medicine, vol. 143, pp. 482-493. https://doi.org/10.1016/j.freeradbiomed.2019.09.005
Chen, Jingwen ; Huang, Zhenqian ; Wu, Xin ; Kang, Jiaqi ; Ren, Yan ; Gao, Wei ; Lu, Xiang ; Wang, Jingmei ; Ding, Weidong ; Nakabeppu, Yusaku ; Fan, Yimei ; Wang, Yaping. / Oxidative stress induces different tissue dependent effects on Mutyh-deficient mice. In: Free Radical Biology and Medicine. 2019 ; Vol. 143. pp. 482-493.
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AU - Gao, Wei

AU - Lu, Xiang

AU - Wang, Jingmei

AU - Ding, Weidong

AU - Nakabeppu, Yusaku

AU - Fan, Yimei

AU - Wang, Yaping

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