Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation

Mito Kanatsu-Shinohara, Takuya Yamamoto, Hidehiro Toh, Yasuhiro Kazuki, Kanako Kazuki, Junichi Imoto, Kazuho Ikeo, Motohiko Oshima, Katsuhiko Shirahige, Atsushi Iwama, Yoichi Nabeshima, Hiroyuki Sasaki, Takashi Shinohara

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3 Citations (Scopus)

Abstract

Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite having shortened telomeres. Aged SSCs showed increased Wnt7b expression, which was associated with decreased Polycomb complex 2 activity. Our results suggest that aberrant Wnt7b expression activated c-jun N-terminal kinase (JNK), which down-regulated mitochondria numbers by suppressing Ppargc1a. Down-regulation of Ppargc1a probably decreased reactive oxygen species and enhanced glycolysis. Analyses of the Klotho-deficient aging mouse model and 2-y-old aged rats confirmed JNK hyperactivation and increased glycolysis. Therefore, not only microenvironment but also intrinsic activation of JNK-mediated glycolysis contributes to SSC aging.

Original languageEnglish
Pages (from-to)16404-16409
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number33
DOIs
Publication statusPublished - Aug 13 2019

All Science Journal Classification (ASJC) codes

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    Kanatsu-Shinohara, M., Yamamoto, T., Toh, H., Kazuki, Y., Kazuki, K., Imoto, J., Ikeo, K., Oshima, M., Shirahige, K., Iwama, A., Nabeshima, Y., Sasaki, H., & Shinohara, T. (2019). Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation. Proceedings of the National Academy of Sciences of the United States of America, 116(33), 16404-16409. https://doi.org/10.1073/pnas.1904980116