2. Academic Validation
  3. Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation

Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation

  • J Hazard Mater. 2024 Mar 27:470:134142. doi: 10.1016/j.jhazmat.2024.134142.
Tian-Tian Wang 1,  Hua-Long Zhu 2,  Kong-Wen Ouyang 1,  Hua Wang 3,  Ye-Xin Luo 1,  Xin-Mei Zheng 1,  Qing Ling 1,  Kai-Wen Wang 1,  Jin Zhang 1,  Wei Chang 1,  Qi Lu 1,  Yu-Feng Zhang 1,  Zhi Yuan 1,  Hao Li 1,  Yong-Wei Xiong 2,  Tian Wei 2,  Hua Wang 4
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.
  • 2 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.
  • 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. Electronic address: wanghuadev@ahmu.edu.cn.
PMID: 38555669 DOI: 10.1016/j.jhazmat.2024.134142
Abstract

Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and Cardiovascular Disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial Reactive Oxygen Species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders.

Keywords

Environmental cadmium; Mitochondrial fusion disorder; Parkin; Testosterone.

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