TY - JOUR
T1 - Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation
AU - Kanatsu-Shinohara, Mito
AU - Yamamoto, Takuya
AU - Toh, Hidehiro
AU - Kazuki, Yasuhiro
AU - Kazuki, Kanako
AU - Imoto, Junichi
AU - Ikeo, Kazuho
AU - Oshima, Motohiko
AU - Shirahige, Katsuhiko
AU - Iwama, Atsushi
AU - Nabeshima, Yoichi
AU - Sasaki, Hiroyuki
AU - Shinohara, Takashi
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Ms. S. Ikeda, M. Kataba, and S. Sakurai for technical assistance. Financial support was provided by the Ministry of Education, Culture, Sports, Science, and Technology, Japan (18H05281, 19H05750, and 17H05639). This research is also supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and AMED-CREST (JP18gm1110008).
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/8/13
Y1 - 2019/8/13
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1904980116
DO - 10.1073/pnas.1904980116
M3 - Article
C2 - 31358627
AN - SCOPUS:85070610832
SN - 0027-8424
VL - 116
SP - 16404
EP - 16409
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -