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 Ayer; Hidesato Ogawa; Eiji Hara; Yoshitsugu Takabatake; Yoshitaka Isaka; Shuhei Nakamura; Tamotsu Yoshimori

doi:10.1016/j.celrep.2022.110444

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

Cell Rep. 2022 Mar 1;38(9):110444. doi: 10.1016/j.celrep.2022.110444.

Authors

Hitomi Yamamoto-Imoto¹, Satoshi Minami², Tatsuya Shioda³, Yurina Yamashita³, Shinsuke Sakai⁴, Shihomi Maeda⁴, Takeshi Yamamoto⁴, Shinya Oki⁵, Mizuki Takashima³, Tadashi Yamamuro¹, Kyosuke Yanagawa⁶, Ryuya Edahiro⁷, Miki Iwatani¹, Mizue So¹, Ayaka Tokumura¹, Toyofumi Abe⁸, Ryoichi Imamura⁸, Norio Nonomura⁸, Yukinori Okada⁹, Donald E Ayer¹⁰, Hidesato Ogawa¹¹, Eiji Hara¹², Yoshitsugu Takabatake⁴, Yoshitaka Isaka⁴, Shuhei Nakamura¹³, Tamotsu Yoshimori¹⁴

Affiliations

¹ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
² Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Department of Nephrology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
³ Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
⁴ Department of Nephrology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
⁵ Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁶ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
⁷ Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
⁸ Department of Urology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
⁹ Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka 565-0871, Japan.
¹⁰ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
¹¹ Laboratory of Nuclear Dynamics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
¹² Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, Osaka 565-0871, Japan; Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan.
¹³ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: shuhei.nakamura@fbs.osaka-u.ac.jp.
¹⁴ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: tamyoshi@fbs.osaka-u.ac.jp.

PMID: 35235784
DOI: 10.1016/j.celrep.2022.110444

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury*
Animals
Autophagy / physiology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cellular Senescence*
Homeostasis
Mice
Mitochondria

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
MondoA protein, mouse