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Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation
Tian-Tian Wang1, Hua-Long Zhu2, Kong-Wen Ouyang1
1Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
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.
Insights
Environmental cadmium exposure lowers testosterone by disrupting mitochondrial fusion in Leydig cells. This study reveals cadmium-induced Parkin translocation causes mitochondrial dysfunction, leading to reduced testosterone synthesis.
Area of Science:
- Endocrinology
- Toxicology
- Mitochondrial Biology
Background:
- Low testosterone (T) is linked to obesity, infertility, depression, and cardiovascular disease.
- Environmental cadmium (Cd) exposure is known to decrease testosterone, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which cadmium exposure induces testosterone decline.
- To investigate the role of mitochondrial dysfunction and Parkin in cadmium-induced testosterone suppression.
Main Methods:
- Established a murine model of cadmium-induced testicular testosterone decline.
- Investigated mitochondrial fusion, Parkin mitochondrial translocation, and MFN1 protein levels.
- Utilized Parkin knockdown and Mito-TEMPO (mtROS inhibitor) to assess causality.
Main Results:
- Cadmium exposure caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes.
- Cadmium-induced decrease in MFN1 protein, mediated by ubiquitin degradation and Parkin translocation, suppressed testosterone synthesis in Leydig cells.
- Testicular Parkin knockdown and Mito-TEMPO treatment mitigated cadmium-induced testosterone decline and mitochondrial dysfunction.
Conclusions:
- Cadmium exposure induces testosterone decline by causing mitochondrial fusion disorder via Parkin-mediated MFN1 degradation.
- Parkin translocation and subsequent mitochondrial dysfunction are key mechanisms in cadmium-induced Leydig cell dysfunction.
- This study provides a novel mechanistic insight into cadmium's effects on testosterone and suggests potential therapeutic targets for androgen disorders.
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