Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.

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

doi:10.1172/jci.insight.150041

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.

Highlights

Mitochondrial oxidative phosphorylation (OXPHOS) is central to energy substrate utilization and ATP production
Sustained oxidative stress is associated with defective mitophagy and elevated IFN-I signaling in over-nutrition
Western blotting revealed that the levels of the mitophagy/autophagy markers, LC3B and p62, were higher during feeding compared to fasting in the liver of chow fed mice

Summary

Introduction

Mitochondrial oxidative phosphorylation (OXPHOS) is central to energy substrate utilization and ATP production. Dysregulated mitochondrial activity, notably increased oxidative stress, is often associated with obesity and metabolic diseases (1-3). Mitochondrial metabolism is intimately linked to inflammatory reactions. This is exemplified by the metabolic reprogramming from oxidative to glycolytic metabolism during bacterial infection, balancing sufficient ATP production to fuel immune responses and the production of reactive oxygen species and synthesis of active metabolites to mediate effector functions of immune cells (4). Other viral sensing pathways, such as toll-like receptor 3 (TLR3), converge on IRF3/IRF7 to regulate the production of type I interferons (IFN-Is), including IFN-b and several subtypes of IFN-a, which induce the expression of IFNstimulated genes (ISGs) in an autocrine or paracrine manner (6, 7). A prior study has demonstrated that increased IFN-I response induces CD8+ T cell-mediated metabolic inflammation in dietinduced obese mice to drive hepatic steatosis and insulin resistance (8). The triggers and cellular origins of IFN-I signaling have not been identified

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