Link discovered between male infertility and self-eating

Osaka, Japan – Androgens—male hormones—are involved in male fertility. However, it has previously been elusive how androgens affect the creation of sperm. Now, a team from Osaka University has found that androgens regulate the levels of a protein called Rubicon to control the breakdown of another protein called GATA4 that is essential for the proper functioning of Sertoli cells.

Androgens become downregulated upon fatherhood, with an associated decrease in fertility, which may occur to focus a father towards caring for his existing offspring. Sertoli cells are a cell type essential for spermatogenesis, or the generation of sperm, that are located in the testes. Until now, it has been unclear how the functions of Sertoli cells are regulated, or how they are affected by androgens.

The protein Rubicon is a regulator of autophagy, or self-eating. The team used genetically modified mice to show that when there are high levels of autophagy in Sertoli cells, there is a decrease in spermatogenesis. They also found that autophagy degrades the “transcription factor” protein GATA4, which is responsible for controlling the expression of Sertoli-cell-related genes.

Rubicon negatively regulates autophagy, so low levels of Rubicon lead to increased autophagy. These low levels and the resultant increased autophagy in the testis led to decreased spermatogenesis. “Rubicon is therefore likely to be responsible for inhibiting the degradation of GATA4 and protecting Sertoli cell function,” explains lead author Tadashi Yamamuro. “Then, Rubicon itself may be regulated by androgens, that act to maintain the levels of Rubicon and GATA4 in cells.” Therefore, it seems that Rubicon’s effect on autophagy may control the amount of GATA4 in various organs during development.

Interestingly, while genetic loss of Rubicon decreases male fertility, Rubicon is known to accumulate with age, and its loss extends lifespan by upregulating autophagy. Increased autophagy is beneficial in terms of age-related diseases and is associated with longevity. “Fertility is known to be negatively correlated with longevity in animals,” says senior author Shuhei Nakamura, “and this regulation of autophagic GATA4 degradation by Rubicon could be one of the underlying mechanisms that reciprocally regulates both fertility and longevity.”

As well as the discovery of this novel mechanism by which Sertoli cells are regulated, some male infertility conditions could well be a result of excess autophagy in Sertoli cells. These findings may therefore aid in the development of treatments for male infertility.

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The article, “Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function,” was published in PLOS Genetics at https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009688 (DOI: https://doi.org/10.1371/journal.pgen.1009688)

About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.

Website: https://resou.osaka-u.ac.jp/en