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Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.
Liou, Yae-Huei; Personnaz, Jean; Jacobi, David; Knudsen, Nelson H; Chalom, Mayer M; Starost, Kyle A; Nnah, Israel C; Lee, Chih-Hao.
Afiliação
  • Liou YH; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Personnaz J; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Jacobi D; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Knudsen NH; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Chalom MM; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Starost KA; Graduate School of Biomedical Sciences, Department of Cellular, Molecular, and Developmental Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
  • Nnah IC; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Lee CH; Department of Molecular Metabolism, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
JCI Insight ; 7(4)2022 02 22.
Article em En | MEDLINE | ID: mdl-35015731
ABSTRACT
Mitophagy and mitochondrial integrated stress response (ISR) are 2 primary protective mechanisms to maintain functional mitochondria. Whether these 2 processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 overexpression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD-fed mice. RNA-Seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis, and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I-stimulated genes through activating transcription factor 5 (Atf5), which inhibits the transactivation activity of interferon regulatory factor 3 (Irf3) known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 overexpression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD-fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA / Regulação da Expressão Gênica / Estresse Oxidativo / Proteínas Mitocondriais / Mitofagia / Fígado / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: JCI Insight Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA / Regulação da Expressão Gênica / Estresse Oxidativo / Proteínas Mitocondriais / Mitofagia / Fígado / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: JCI Insight Ano de publicação: 2022 Tipo de documento: Article