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 3

Fis1 overexpression induces an ISR.

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Fis1 overexpression induces an ISR. (A) Functional clustering analysis o...
(A) Functional clustering analysis of 1236 genes upregulated (FDR P < 0.001) by Ad-Fis1 versus Ad-LacZ in primary hepatocytes identified by RNA-Seq. n = 4 in 1 experiment. (B) Validation of RNA-Seq results for ISR genes in UPRmt, UPRer, tRNA synthesis, and 1-carbon metabolism (1-C) pathway in primary hepatocytes infected with Ad-Fis1 or Ad-LacZ by real-time qPCR. n = 4–6. (C) HOMER motif analysis to identify potential transcription factor binding sites on promoters of Ad-Fis1–upregulated genes. (D) Assessing the effects of knocking down Atf5 or Fis1 on ISR gene expression in hepatocytes by real-time PCR analysis. Primary hepatocytes were infected with Ad-shCtl, Ad-shAtf5, or Ad-shFis1 and cells were harvested 48 hours after infection. 36b4 was used for normalization to determine the relative expression. n = 3, repeated 4 times. (E) Assessing Atf5 as a Fis1 downstream effector in regulating hepatic ISR gene 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. Values are presented as mean ± SEM. Significance of B and E were determined by unpaired, 2-tailed Student’s t test; and of D by 1-way ANOVA followed by Holm-Šidák multiple comparisons test. *P < 0.05; #P < 0.01; $P < 0.001.