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  3. m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure

m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure

  • Sci Total Environ. 2024 Jun 25:931:172938. doi: 10.1016/j.scitotenv.2024.172938.
Kong-Wen Ouyang 1,  Tian-Tian Wang 2,  Hua Wang 3,  Ye-Xin Luo 2,  Yi-Fan Hu 2,  Xin-Mei Zheng 2,  Qing Ling 2,  Kai-Wen Wang 2,  Yong-Wei Xiong 4,  Jin Zhang 2,  Wei Chang 2,  Yu-Feng Zhang 2,  Zhi Yuan 2,  Hao Li 2,  Lan Gao 4,  De-Xiang Xu 4,  Hua-Long Zhu 5,  Lan Yang 6,  Hua Wang 7
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Center of Prenatal Diagnosis, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi 214000, China.
  • 2 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • 3 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Department of Respiratory Medicine, Anhui Provincial Children's Hospital, Hefei, Anhui 230000, China.
  • 4 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of The People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China.
  • 5 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of The People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: zhuhualongdev@126.com.
  • 6 Department of Toxicology, School of Public Health, Anhui Medical University, China; Center of Prenatal Diagnosis, Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi 214000, China. Electronic address: lilylan5930@sina.com.
  • 7 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of The People's Republic of China, No 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: wanghuadev@ahmu.edu.cn.
PMID: 38703850 DOI: 10.1016/j.scitotenv.2024.172938
Abstract

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as Cell Apoptosis and Necrosis. However, as a new type of cell death, the role and mechanism of Pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent Pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent Pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent Pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and Pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent Pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

Keywords

Environmental cadmium; LONP1; Pyroptosis; Testicular germ cells; m6A.

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