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Mitochondrial Stress in Non-alcoholic Fatty Liver Disease
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Mitochondrial Stress in Non-alcoholic Fatty Liver Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 19924

Special Issue Editors

Prof. Dr. Paulo J. Oliveira

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Guest Editor
CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal
Interests: heart; liver; mitochondria; metabolism; mitochondria-targeted interventions; physical activity; apoptosis; biomarkers for mitochondrial dysfunction
Prof. Dr. Joan Roselló-Catafau

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Guest Editor
Experimental Hepatic Ischemia-Reperfusion Unit, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain
Interests: organ (liver, pancreas, small intestine, kidney) transplantation; cell signaling molecular mechanisms in organ transplantation; graft therapeutics; preservation and preservation solutions
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Carlos Marques Palmeira

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Guest Editor
1. Department of Life Sciences, University of Coimbra, Portugal
2. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Portugal
Interests: liver, muscle, adipose tissue; ischemia/reperfusion; mitochondria; steatosis; mitochondrial signalling and bioenergetics; mitochondrial dynamics; mitohormesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues

Despite over 30 years of major progress in the knowledge and management of liver disease, approximately 29 million people in the European Union currently suffer from a chronic liver condition, with cirrhosis and primary liver cancer representing the end-stage of liver pathology. The four leading causes of cirrhosis and primary liver cancer in Europe are harmful alcohol consumption, viral hepatitis B and C, and non-alcoholic fatty liver disease (NAFLD). The latter, encompassing non-alcoholic steatohepatitis (NASH), is now among the most prevalent chronic liver diseases, with particularly steep increases in Western Societies.

NAFLD has risen rapidly in parallel with the recent surge in obesity and Type 2 diabetes mellitus (T2DM). Available data suggests its prevalence rate to be 2–44% in the general European population and 42.6–69.5% in people with type 2 diabetes mellitus (T2DM). This wide range of estimates in part reflects the poor specificity and accuracy of current clinical screening methods. Moreover, there is no therapeutic consensus for NAFLD/NASH treatment at present, which is worsened by the fact that biomarkers that inform hepatic metabolic/mitochondrial function in NAFLD are lacking.  NAFLD is predicted to be the primary cause for liver transplants by 2020, representing a major potential threat to public health in Europe and in the world.  

Hence, novel and innovative NAFLD will reap substantial societal benefits and provide commercial opportunities. While NAFLD development involves the interplay of nutritional and intrinsic factors, the gut–liver axis and hepatic mitochondrial remodelling are two critical mediators in the overall process, which often are inter-connected but poorly explored. Mitochondrial stress responses are considered an important fulcrum of the progressive hepatic degeneration observed in NAFLD.

This Special Issue will publish top quality original papers, mini and full reviews, and perspectives based on basic and translational research, clinical implementation, technology development and transfer, and social outreach-focused papers.

The general premise of the research background for this special edition is that NAFLD pathogenesis and progression involves nutrient, inflammatory, and oxidative stress factors that directly or indirectly impair mitochondrial metabolic activity and energy generation in the liver, thus resulting in mitochondrial stress. Therefore, characterizing the underlying mechanisms of metabolic and gut-liver axis dysfunction, identifying biomarkers that inform mitochondrial/metabolic status, and designing interventions for restoration of normal metabolic activity in NAFLD patients are the central goals of this edition.

Prof. Dr. Paulo J. Oliveira
Prof. Dr. Joan Rosello-Catafau
Prof. Dr. Carlos Marques Palmeira
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (3 papers)

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Research

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15 pages, 1971 KiB  
Article
The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function
by João S. Teodoro, João A. Amorim, Ivo F. Machado, Ana C. Castela, Clemens Steegborn, David A. Sinclair, Anabela P. Rolo and Carlos M. Palmeira
Int. J. Mol. Sci. 2020, 21(14), 4896; https://doi.org/10.3390/ijms21144896 - 11 Jul 2020
Cited by 4 | Viewed by 3815
Abstract
Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. [...] Read more.
Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD+-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I/R injury. Full article
(This article belongs to the Special Issue Mitochondrial Stress in Non-alcoholic Fatty Liver Disease)
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16 pages, 2122 KiB  
Article
Aspalathin-Enriched Green Rooibos Extract Reduces Hepatic Insulin Resistance by Modulating PI3K/AKT and AMPK Pathways
by Sithandiwe E. Mazibuko-Mbeje, Phiwayinkosi V. Dludla, Candice Roux, Rabia Johnson, Samira Ghoor, Elizabeth Joubert, Johan Louw, Andy R. Opoku and Christo J. F. Muller
Int. J. Mol. Sci. 2019, 20(3), 633; https://doi.org/10.3390/ijms20030633 - 1 Feb 2019
Cited by 60 | Viewed by 6499
Abstract
We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the [...] Read more.
We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways. Full article
(This article belongs to the Special Issue Mitochondrial Stress in Non-alcoholic Fatty Liver Disease)
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Review

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35 pages, 896 KiB  
Review
Antioxidant Versus Pro-Apoptotic Effects of Mushroom-Enriched Diets on Mitochondria in Liver Disease
by Adriana Fontes, Mireia Alemany-Pagès, Paulo J. Oliveira, João Ramalho-Santos, Hans Zischka and Anabela Marisa Azul
Int. J. Mol. Sci. 2019, 20(16), 3987; https://doi.org/10.3390/ijms20163987 - 16 Aug 2019
Cited by 20 | Viewed by 8962
Abstract
Mitochondria play a central role in non-alcoholic fatty liver disease (NAFLD) progression and in the control of cell death signalling during the progression to hepatocellular carcinoma (HCC). Associated with the metabolic syndrome, NAFLD is mostly driven by insulin-resistant white adipose tissue lipolysis that [...] Read more.
Mitochondria play a central role in non-alcoholic fatty liver disease (NAFLD) progression and in the control of cell death signalling during the progression to hepatocellular carcinoma (HCC). Associated with the metabolic syndrome, NAFLD is mostly driven by insulin-resistant white adipose tissue lipolysis that results in an increased hepatic fatty acid influx and the ectopic accumulation of fat in the liver. Upregulation of beta-oxidation as one compensatory mechanism leads to an increase in mitochondrial tricarboxylic acid cycle flux and ATP generation. The progression of NAFLD is associated with alterations in the mitochondrial molecular composition and respiratory capacity, which increases their vulnerability to different stressors, including calcium and pro-inflammatory molecules, which result in an increased generation of reactive oxygen species (ROS) that, altogether, may ultimately lead to mitochondrial dysfunction. This may activate further pro-inflammatory pathways involved in the progression from steatosis to steatohepatitis (NASH). Mushroom-enriched diets, or the administration of their isolated bioactive compounds, have been shown to display beneficial effects on insulin resistance, hepatic steatosis, oxidative stress, and inflammation by regulating nutrient uptake and lipid metabolism as well as modulating the antioxidant activity of the cell. In addition, the gut microbiota has also been described to be modulated by mushroom bioactive molecules, with implications in reducing liver inflammation during NAFLD progression. Dietary mushroom extracts have been reported to have anti-tumorigenic properties and to induce cell-death via the mitochondrial apoptosis pathway. This calls for particular attention to the potential therapeutic properties of these natural compounds which may push the development of novel pharmacological options to treat NASH and HCC. We here review the diverse effects of mushroom-enriched diets in liver disease, emphasizing those effects that are dependent on mitochondria. Full article
(This article belongs to the Special Issue Mitochondrial Stress in Non-alcoholic Fatty Liver Disease)
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