BACH1 inhibits senescence, obesity, and short lifespan by ferroptotic FGF21 secretion
Hironari Nishizawa,
Mitsuyo Matsumoto,
Mie Yamanaka,
Riko Irikura,
Kazuma Nakajima,
Keisuke Tada,
Yoshiaki Nakayama,
Morichika Konishi,
Nobuyuki Itoh,
Ryo Funayama,
Keiko Nakayama,
Kazuhiko Igarashi
Affiliations
Hironari Nishizawa
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Corresponding author
Mitsuyo Matsumoto
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Mie Yamanaka
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Gladstone Institute of Neurological Disease, Gladstone Institute, San Francisco, CA 94158, USA
Riko Irikura
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Kazuma Nakajima
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Keisuke Tada
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Yoshiaki Nakayama
Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Hyogo 658-8558, Japan
Morichika Konishi
Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Hyogo 658-8558, Japan
Nobuyuki Itoh
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606-8501, Japan
Ryo Funayama
Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Department of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Keiko Nakayama
Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Department of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Kazuhiko Igarashi
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Corresponding author
Summary: Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation. A model cell system is constructed to induce ferroptosis by re-expressing the transcription factor BACH1, a potent ferroptosis inducer, in immortalized mouse embryonic fibroblasts (iMEFs). The transfer of the culture supernatant from ferroptotic iMEFs activates the proliferation of hepatoma cells and other fibroblasts and suppresses cellular senescence-like features. The BACH1-dependent secretion of the longevity factor FGF21 is increased in ferroptotic iMEFs. The anti-senescent effects of the culture supernatant from these iMEFs are abrogated by Fgf21 knockout. BACH1 activates the transcription of Fgf21 by promoting ferroptotic stress and increases FGF21 protein expression by suppressing its autophagic degradation through transcriptional Sqstm1 and Lamp2 repression. The BACH1-induced ferroptotic FGF21 secretion suppresses obesity in high-fat diet-fed mice and the short lifespan of progeria mice. The inhibition of these aging-related phenotypes can be physiologically significant regarding ferroptosis.
