Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis

Hitomi Yamamoto-Imoto, Satoshi Minami, Tatsuya Shioda, Yurina Yamashita, Shinsuke Sakai, Shihomi Maeda, Takeshi Yamamoto, Shinya Oki, Mizuki Takashima, Tadashi Yamamuro, Kyosuke Yanagawa, Ryuya Edahiro, Miki Iwatani, Mizue So, Ayaka Tokumura, Toyofumi Abe, Ryoichi Imamura, Norio Nonomura, Yukinori Okada, Donald E. AyerHidesato Ogawa, Eiji Hara, Yoshitsugu Takabatake, Yoshitaka Isaka, Shuhei Nakamura, Tamotsu Yoshimori

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.

Original languageEnglish
Article number110444
JournalCell Reports
Volume38
Issue number9
DOIs
StatePublished - 1 Mar 2022
Externally publishedYes

Keywords

  • C. elegans
  • MondoA
  • Rubicon
  • aging
  • autophagy
  • cellular senescence
  • kidney
  • mitochondrial homeostasis
  • mml-1
  • peroxiredoxin 3

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