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Published on: September 17, 2019
An SOD1 deficiency aggravates proteasome inhibitor bortezomib-induced testicular damage in mice
Takujiro Homma1, Junichi Fujii1
1Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.
Abstract:
Proteasomes play a key role in maintaining cellular homeostasis by the proteolytic removal of proteins, including ubiquitinated proteins and/or oxidatively-damaged proteins. The proteasome inhibitor bortezomib (BTZ) has been reported to exert testicular toxicity in mice. In the current study, we treated SOD1-knockout (KO) mice with BTZ and investigated the issue of whether oxidative stress is involved in the development of testicular toxicity. The BTZ treatment significantly increased superoxide production and cell death in the testes of SOD1-KO mice compared to wild-type (WT) mice. We also found that high levels of both ubiquitinated proteins and p62 accumulated and underwent aggregation in the seminiferous tubules of BTZ-injected SOD1-KO mice. Furthermore, the proteolytic activities of proteasomes were significantly decreased in the testes of BTZ-injected SOD1-KO mice compared to their WT counterparts. These results suggest that a combination of oxidative stress caused by an SOD1 deficiency and proteasome inhibition by BTZ accelerates the impairment of proteasomes, which results in severe testicular damage in SOD1-KO mice.
Insights
Proteasome inhibitor bortezomib causes severe testicular damage in SOD1-knockout mice by increasing oxidative stress and impairing proteasome function. This highlights the critical role of SOD1 in mitigating proteasome dysfunction and preventing toxicity.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Proteasomes are crucial for cellular homeostasis, degrading damaged proteins.
- Proteasome inhibitors like bortezomib can cause testicular toxicity.
- Oxidative stress is implicated in various cellular dysfunctions.
Purpose of the Study:
- To investigate the role of oxidative stress in bortezomib-induced testicular toxicity.
- To examine the impact of bortezomib on proteasome function in SOD1-knockout mice.
Main Methods:
- Treatment of SOD1-knockout (KO) and wild-type (WT) mice with bortezomib (BTZ).
- Assessment of superoxide production, cell death, protein aggregation (ubiquitinated proteins, p62), and proteasome activity in testicular tissues.
- Comparison of BTZ effects between SOD1-KO and WT mice.
Main Results:
- BTZ significantly increased superoxide production and cell death in SOD1-KO mice testes compared to WT mice.
- Accumulation and aggregation of ubiquitinated proteins and p62 were observed in BTZ-treated SOD1-KO mice.
- Proteasome proteolytic activity was significantly reduced in BTZ-treated SOD1-KO mice testes.
Conclusions:
- A deficiency in SOD1 exacerbates bortezomib-induced oxidative stress.
- Combined oxidative stress and proteasome inhibition accelerate proteasome impairment.
- This leads to severe testicular damage in SOD1-knockout mice.
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