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

Review Article Endocrinol Metab 2019;34:39-46 https://doi.org/10.3803/EnM.2019.34.1.39 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 proteome, have established the importance of mitochondrial quality control in the development and progression of metabolic liver diseases, 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 Metabolic liver diseases constitute a major health burden. Among them, fatty liver, characterized by the presence of large lipid vacuoles within the cytosol in hepatocytes, is a benign condition, but pathognomonic for non-alcoholic fatty liver disease (NAFLD) and alcoholic liver injury. Despite the globally widespread incidence and prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), almost no pharmacotherapeutic options are available for these conditions. In approximately 10% of patients, NAFLD can progress in the long term to NASH, which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma [1]. Liver parenchymal cells display a prominent eosinophilic cytoplasm upon hematoxylin-eosin staining, indicating that they Received: 5 January 2019, Revised: 16 January 2019, Accepted: 24 January 2019 Corresponding author: Hyon-Seung Yi Research Center for Endocrine and Metabolic Diseases, Chungnam National University College of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea Tel: +82-42-280-6994, Fax: +82-42-280-6990, E-mail: have abundant mitochondria [2]. This means that mitochondrial dysfunction in hepatocytes results in cellular damage, which is linked to fatty liver diseases. For instance, chronic alcohol consumption alters mitochondrial oxidative phosphorylation in the liver by suppressing the synthesis of respiratory complex proteins [3], and hepatic mitochondria are structurally and functionally altered in NAFLD [4]. Thus, it is not surprising that mitochondrial dysfunction involving structural and molecular alterations leads to metabolic disturbances, potentially resulting in metabolic liver diseases, ranging from fatty liver to hepatocellular carcinoma. Recently, one of the most remarkable scientific discoveries in mitochondrial biology has been the identification of the mitochondrial unfolded protein response (UPRmt), a retrograde mitochondria-to-nucleus signaling pathway induced by mitochonCopyright © 2019 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu tion, and reproduction in any medium, provided the original work is properly cited. 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 mitochondria 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, fibroblast growth factor 21; GDF15, growth differentiation factor 15; Hspd1, heat shock protein family D member 1; ClpP, caseinolytic peptidase P; Lonp1, LON protease 1. drial proteotoxic stress (Fig. 1). The UPRmt was first identified in the late 1990s, and is an area of increased scientific interest for research on aging-related degenerative diseases and metabolic disorders in organisms ranging from worms to mammals [5]. Regarding liver diseases, eliciting the UPRmt or mitohormetic factors not only inhibits the progression of NAFLD [6], but also ameliorates hepatic fibrosis and alcoholic liver injury in mice [7]. In this review, we summarize the current knowledge on the implications of mitochondrial function and protein homeostasis in the development of metabolic liver diseases, including NAFLD/NASH, alcoholic liver disease, and fibrosis. We also discuss mitochondrial proteostasis and mitohormesis as new therapeutic targets for the treatment of a broad spectrum of metabolic liver diseases. MITOCHONDRIAL BIOLOGY IN FATTY LIVER AND FIBROTIC LIVER DISEASES Metabolic liver diseases are associated with functional alterations of mitochondrial oxidative phosphorylation [8,9]. For example, hepatic depletion of mitochondrial flavoprotein apoptosis inducing factor induced deficient oxidative phosphorylation, but resulted in the improvement of hepatic insulin resistance in mice [10]. In contrast, alcohol-mediated mitochondrial DNA (mtDNA) damage deteriorated cellular energy metabolism via enhanced formation of reactive oxygen species (ROS) in mice 40 www.e-enm.org [11]. Moreover, in another mouse study, carbon tetrachloride (CCl4) decreased mitochondrial respiratory chain complex IV activity and reduced hepatic mtDNA [12]. Furthermore, the ROS produced by cytochrome P450 2E1-mediated CCl4 metabolism has been found to bind to mtDNA and promote lipid peroxidation, leading to mtDNA degradation [12]. Thus, ROS-mediated hepatocellular oxidative damage is implicated in the progression of NAFLD and fibrotic liver diseases. RECENT INSIGHTS INTO MITOCHONDRIAL PROTEOSTASIS AND MITOKINES Recent investigations in worms and mammals have demonstrated that genetic inhibition of mitochondrial oxidative phosphorylation activated the UPRmt, leading to an increased lifespan and improved metabolic phenotypes [13]. This suggests that modest mitochondrial inhibition paradoxically improves the metabolic phenotype and lifespan across species. This phenomenon, which is defined as mitochondrial homeostasis, or mitohormesis, involves the UPRmt and plays a prominent role in aging and degenerative diseases. Many scientists are trying to establish the role of the UPRmt in mammalian cells and systems, and to characterize its possible role in mitohormesis [5]. The mitochondrial chaperones and proteases predicted to be involved in the regulation of mitochondrial protein homeos (...truncated)