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

Research output: Contribution to journalArticle

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

Fingerprint

Glycolysis
Stem Cells
JNK Mitogen-Activated Protein Kinases
Cell Aging
Telomere Shortening
Testis
Reactive Oxygen Species
Mitochondria
Down-Regulation
Transplantation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Kanatsu-Shinohara, M., Yamamoto, T., Toh, H., Kazuki, Y., Kazuki, K., Imoto, J., ... 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

Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation. / Kanatsu-Shinohara, Mito; Yamamoto, Takuya; Toh, Hidehiro; Kazuki, Yasuhiro; Kazuki, Kanako; Imoto, Junichi; Ikeo, Kazuho; Oshima, Motohiko; Shirahige, Katsuhiko; Iwama, Atsushi; Nabeshima, Yoichi; Sasaki, Hiroyuki; Shinohara, Takashi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 33, 13.08.2019, p. 16404-16409.

Research output: Contribution to journalArticle

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, vol. 116, no. 33, pp. 16404-16409. https://doi.org/10.1073/pnas.1904980116
Kanatsu-Shinohara, Mito ; Yamamoto, Takuya ; Toh, Hidehiro ; Kazuki, Yasuhiro ; Kazuki, Kanako ; Imoto, Junichi ; Ikeo, Kazuho ; Oshima, Motohiko ; Shirahige, Katsuhiko ; Iwama, Atsushi ; Nabeshima, Yoichi ; Sasaki, Hiroyuki ; Shinohara, Takashi. / Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 33. pp. 16404-16409.
@article{8384049e3b024404bad28c434d447922,
title = "Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation",
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.",
author = "Mito Kanatsu-Shinohara and Takuya Yamamoto and Hidehiro Toh and Yasuhiro Kazuki and Kanako Kazuki and Junichi Imoto and Kazuho Ikeo and Motohiko Oshima and Katsuhiko Shirahige and Atsushi Iwama and Yoichi Nabeshima and Hiroyuki Sasaki and Takashi Shinohara",
year = "2019",
month = "8",
day = "13",
doi = "10.1073/pnas.1904980116",
language = "English",
volume = "116",
pages = "16404--16409",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85070610832&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070610832&partnerID=8YFLogxK

U2 - 10.1073/pnas.1904980116

DO - 10.1073/pnas.1904980116

M3 - Article

C2 - 31358627

AN - SCOPUS:85070610832

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

SN - 0027-8424

IS - 33

ER -