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Implications of Mitochondrial Unfolded Protein Response and Mitokines: a Perspective on Fatty Liver Diseases

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Implications of Mitochondrial Unfolded Protein Response and Mitokines: a Perspective on Fatty Liver Diseases Review Endocrinol Metab 2019;34:39-46 https://doi.org/10.3803/EnM.2019.34.1.39 Article pISSN 2093-596X · eISSN 2093-5978 Implications of Mitochondrial Unfolded Protein Response and Mitokines: A Perspective on Fatty Liver Diseases Hyon-Seung Yi Research Center for Endocrine and Metabolic Diseases, Chungnam National University College of Medicine, Daejeon, Korea The signaling network of the mitochondrial unfolded protein response (UPRmt) and mitohormesis is a retrograde signaling pathway through which mitochondria-to-nucleus communication occurs in organisms. Recently, it has been shown that the UPRmt is closely associated with metabolic disorders and conditions involving insulin resistance, such as alcoholic and non-alcoholic fatty liver and fibrotic liver disease. Scientific efforts to understand the UPRmt and mitohormesis, as well as to establish the mitochondrial pro- teome, have established the importance of mitochondrial quality control in the development and progression of metabolic liver dis- eases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In this review, we integrate and discuss the recent data from the literature on the UPRmt and mitohormesis in metabolic liver diseases, including NAFLD/NASH and fibrosis. Keywords: Mitochondria; Fatty liver; Metabolism; Obesity; Insulin resistance INTRODUCTION have abundant mitochondria [2]. This means that mitochondrial dysfunction in hepatocytes results in cellular damage, which is Metabolic liver diseases constitute a major health burden. linked to fatty liver diseases. For instance, chronic alcohol con- Among them, fatty liver, characterized by the presence of large sumption alters mitochondrial oxidative phosphorylation in the lipid vacuoles within the cytosol in hepatocytes, is a benign liver by suppressing the synthesis of respiratory complex pro- condition, but pathognomonic for non-alcoholic fatty liver dis- teins [3], and hepatic mitochondria are structurally and func- ease (NAFLD) and alcoholic liver injury. Despite the globally tionally altered in NAFLD [4]. Thus, it is not surprising that mi- widespread incidence and prevalence of NAFLD and non-alco- tochondrial dysfunction involving structural and molecular al- holic steatohepatitis (NASH), almost no pharmacotherapeutic terations leads to metabolic disturbances, potentially resulting in options are available for these conditions. In approximately metabolic liver diseases, ranging from fatty liver to hepatocellu- 10% of patients, NAFLD can progress in the long term to lar carcinoma. NASH, which can lead to fibrosis, cirrhosis, and hepatocellular Recently, one of the most remarkable scientific discoveries in carcinoma [1]. mitochondrial biology has been the identification of the mito- Liver parenchymal cells display a prominent eosinophilic cy- chondrial unfolded protein response (UPRmt), a retrograde mito- toplasm upon hematoxylin-eosin staining, indicating that they chondria-to-nucleus signaling pathway induced by mitochon- Received: 5 January 2019, Revised: 16 January 2019, Copyright © 2019 Korean Endocrine Society Accepted: 24 January 2019 This is an Open Access article distributed under the terms of the Creative Com- Corresponding author: Hyon-Seung Yi mons Attribution Non-Commercial License (http://creativecommons.org/ Research Center for Endocrine and Metabolic Diseases, Chungnam National licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu- University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, tion, and reproduction in any medium, provided the original work is properly Korea cited. Tel: +82-42-280-6994, Fax: +82-42-280-6990, E-mail: [email protected] www.e-enm.org 39 Yi HS Fig. 1. Scheme depicting the mitochondrial unfolded protein response (UPRmt) and mitokines. As a cell autonomous response, damaged mi- tochondria within a cell communicate to the nucleus via retrograde signaling. In contrast, mitokines (as a cell non-autonomous factor) are induced during the UPRmt and are secreted from cells affected by mitochondrial stress. OXPHOS, oxidative phosphorylation; FGF21, fibro- blast growth factor 21; GDF15, growth differentiation factor 15; Hspd1, heat shock protein family D member 1; ClpP, caseinolytic pepti- dase P; Lonp1, LON protease 1. drial proteotoxic stress (Fig. 1). The UPRmt was first identified [11]. Moreover, in another mouse study, carbon tetrachloride in the late 1990s, and is an area of increased scientific interest (CCl4) decreased mitochondrial respiratory chain complex IV for research on aging-related degenerative diseases and meta- activity and reduced hepatic mtDNA [12]. Furthermore, the bolic disorders in organisms ranging from worms to mammals ROS produced by cytochrome P450 2E1-mediated CCl4 metab- [5]. Regarding liver diseases, eliciting the UPRmt or mitohor- olism has been found to bind to mtDNA and promote lipid per- metic factors not only inhibits the progression of NAFLD [6], oxidation, leading to mtDNA degradation [12]. Thus, ROS-me- but also ameliorates hepatic fibrosis and alcoholic liver injury in diated hepatocellular oxidative damage is implicated in the pro- mice [7]. gression of NAFLD and fibrotic liver diseases. In this review, we summarize the current knowledge on the implications of mitochondrial function and protein homeostasis RECENT INSIGHTS INTO MITOCHONDRIAL in the development of metabolic liver diseases, including PROTEOSTASIS AND MITOKINES NAFLD/NASH, alcoholic liver disease, and fibrosis. We also discuss mitochondrial proteostasis and mitohormesis as new Recent investigations in worms and mammals have demonstrat- therapeutic targets for the treatment of a broad spectrum of met- ed that genetic inhibition of mitochondrial oxidative phosphory- abolic liver diseases. lation activated the UPRmt, leading to an increased lifespan and improved metabolic phenotypes [13]. This suggests that modest MITOCHONDRIAL BIOLOGY IN FATTY mitochondrial inhibition paradoxically improves the metabolic LIVER AND FIBROTIC LIVER DISEASES phenotype and lifespan across species. This phenomenon, which is defined as mitochondrial homeostasis, or mitohorme- Metabolic liver diseases are associated with functional altera- sis, involves the UPRmt and plays a prominent role in aging and tions of mitochondrial oxidative phosphorylation [8,9]. For ex- degenerative diseases. Many scientists are trying to establish the ample, hepatic depletion of mitochondrial flavoprotein apopto- role of the UPRmt in mammalian cells and systems, and to char- sis inducing factor induced deficient oxidative phosphorylation, acterize its possible role in mitohormesis [5]. The mitochondrial but resulted in the improvement of hepatic insulin resistance in chaperones and proteases predicted to be involved in the regula- mice [10]. In contrast, alcohol-mediated mitochondrial DNA tion of mitochondrial protein homeostasis may play a pivotal (mtDNA) damage deteriorated cellular energy metabolism via role in the modulation of fatty liver diseases in mammalian sys- enhanced formation of reactive oxygen species (ROS) in mice tems [5]. While elucidation of the UPRmt has contributed to a 40 www.e-enm.org Copyright © 2019 Korean Endocrine Society Mitochondrial Response in Fatty Liver Diseases greater understanding of the role of mitochondria in stress adap- quality control. Similar to chaperones, mitochondrial proteases tation and lifespan regulation, important questions remain unan- are predicted to be involved in the regulation of mitochondrial swered about the role of the UPRmt in the development of fatty protein homeostasis, thereby playing an essential role in the liver and fibrotic liver diseases. modulation of metabolic diseases across species. The inner mi- tochondrial membrane protease OMA1 zinc metallopeptidase ASPECTS OF THE CELL AUTONOMOUS (OMA1) plays an essential role in the proteolytic inactivation of RESPONSE the GTPase optic atrophy protein 1 (OPA1), which regulates mitochondrial quality control. A remarkable level of steatosis Mitochondrial chaperones was found in the liver of Oma1-deficient mice on a normal Mitochondrial chaperones and proteases play important roles in chow diet, and was further significantly elevated under a high- normal cellular function and survival, which are required for fat diet [25]. OPA1 is required for fusion of the outer mitochon- maintaining organismal homeostasis. Emerging studies have drial membrane and inner mitochondrial membrane in mam- shown that the biological effects of UPRmt activation in condi- mals [26]. Acute Opa1 deletion in skeletal muscle was found to tions of increased mitochondrial proteotoxic stress are mediated induce hepatic steatosis and high levels of inflammatory cyto- by both cell autonomous and cell non-autonomous factors [14]. kines in mice [27]. Mitofusin-2-mediated proteolytic inactiva- In the liver, heat shock protein 60 (HSP60) is involved in tion of Opa1 was found to be associated with mitochondria-en- NAFLD/NASH, chronic hepatitis, and liver cancer [15]. Hsp60 doplasmic reticulum contact assembly in the postprandial liver works as a major defense system against proteotoxic cellular [28]. LON protease (also known as LONP1) is an ATP-depen- damage during alcoholic liver injury [16]. Heat shock protein dent serine protease that is essential for mitochondrial protein family D member 1 (Hspd1) was also found to be an essential homeostasis within the mitochondrial matrix. Reduction of factor in regulating the inflammatory response and cell prolifer- LONP1 by small interfering
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