Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis
Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H. Knudsen, Mayer M. Chalom, Kyle A. Starost, Israel C. Nnah, Chih-Hao Lee
Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H. Knudsen, Mayer M. Chalom, Kyle A. Starost, Israel C. Nnah, Chih-Hao Lee
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Research Article Metabolism

Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis

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.

Authors

Yae-Huei Liou, Jean Personnaz, David Jacobi, Nelson H. Knudsen, Mayer M. Chalom, Kyle A. Starost, Israel C. Nnah, Chih-Hao Lee

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Figure 2

Hepatic Fis1 overexpression improves glucose homeostasis.

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Hepatic Fis1 overexpression improves glucose homeostasis. (A) Levels of ...
(A) Levels of fasting glucose and serum lipids of Ad-LacZ– (control) or Ad-Fis1–infected male mice on a HFD for 4 weeks. Mice were fasted for 4 hours. n = 6–7, repeated in 2 cohorts. (B) GTT (left) and ITT (right) of Ad-LacZ or Ad-Fis1 infected male mice fed a HFD for 4 weeks. n = 7. (C) Electron flow assay using Seahorse bioanalyzer with mitochondria isolated from livers of Ad-LacZ– and Ad-Fis1–infected HFD-fed mice. Complex I (C-I) respiration was measured using pyruvate and malate as substrates and blocked with rotenone. Complex II (C-II) was measured using succinate as substrate and blocked with antimycin A. Complex IV (C-IV) respiration was measured by injecting tetramethyl-p-phenylenediamine/ascorbate. n = 5. OCR, oxygen consumption rate. (D) Protein carbonylation in livers of Ad-Lacz– or Ad-Fis1–infected mice. n = 4-5. (E) Liver TG content of Ad-LacZ– and Ad-Fis1–infected mice. n = 6-7. (F) GTT and ITT of Ad-GFP– (control) or Ad-Fis1–infected HFD-fed male mice (12 weeks HFD). n = 6 for 1 cohort. (G) Immunoblotting showing LC3B and Fis1 protein levels. HFD-fed male mice (12 weeks HFD) were infected with Ad-LacZ or Ad-Fis1. Liver samples were collected 7 days after infection. Actb protein level served as a loading control. n = 5. (H) Relative mROS production determined by MitoSOX Red. Mitochondria were isolated from livers of mice 7 days after infection. Ad-GFP was set as 1. n = 6. Values are presented as mean ± SEM. Significance was determined by 2-way ANOVA for GTT and ITT and unpaired, 2-tailed Student’s t test for 2 group comparisons. *P < 0.05; #P < 0.01; $P < 0.001.