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 4

The Fis1-Atf5 axis of the integrated response suppresses IFN-I signaling.

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The Fis1-Atf5 axis of the integrated response suppresses IFN-I signaling...
(A) Functional clustering analysis of 1384 genes downregulated (FDR P < 0.001) by Ad-Fis1 versus Ad-LacZ in primary hepatocytes identified by RNA-Seq. n = 4 in 1 experiment. (B) HOMER motif analysis to identify potential transcription factor binding sites on promoters of Ad-Fis1 downregulated genes. (C) Relative expression of IFN-stimulated genes in the liver of HFD-fed (12 weeks) mice infected with Ad-GFP or Ad-Fis1. Relative expression in Ad-GFP control was set as 1. n = 4-5, for 1 cohort. (D) Assessing Atf5 as a Fis1 downstream effector in regulating hepatic ISG expression using real-time PCR. Primary hepatocytes were infected with Ad-shCtl or Ad-shAtf5; 8 hours later, cells were washed and infected with Ad-GFP or Ad-Fis1. Hepatocytes were cultured for an additional 40 hours. n = 3, repeated twice. (E) Tlr3, Ifnb1, and Ifitm3 gene expression (n = 3) and (F) IFN-β protein secretion (n = 6) in primary hepatocytes from mice fed a HFD for 6 weeks. Hepatocytes were infected with Ad-LacZ, Ad-Fis1, or Ad-Atf5 overnight, followed by transfection with/without 100 ng/well Poly I:C for 16 hours. Supernatant IFN-β concentration was normalized to cellular protein content. Experiments repeated 4 times. Values are presented as mean ± SEM. Significance of C and D were determined by unpaired, 2-tailed Student’s t test; and of E and F by 1-way ANOVA followed by Holm-Šidák multiple comparisons test. *P < 0.05; #P < 0.01; $P < 0.001.