Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic–lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.
Highlights
The loss of mitochondrial dynamics, the accumulation of damaged mitochondria and the remodeling of mitochondrial activities may lead to metabolic reprogramming of hepatocytes, characterized by the switch towards the Warburg effect, mutagenesis, epithelial–mesenchymal transition (EMT) and several strategies of tumor escape from apoptosis in order to promote the compensatory proliferation and Hepatocellular carcinoma (HCC) onset
The main goal of the present work will be to summarize the main aspects related to nonalcoholic fatty liver disease (NAFLD)–HCC pathophysiology driven by mitochondrial failure and the current knowledge about mitochondrial dynamics, which could lay the groundwork for the development of new therapeutic approaches to prevent and/or manage NAFLD progression towards HCC
In a cross-sectional study, it was observed that NAFLD–HCC patients showed an enrichment of rare genetic variants in Regulator of telomere elongation helicase 1 (RTEL1) and Telomeric repeat binding factor 2 (TERF2) genes, which are involved in telomere preservation, and in RB1, which mediates the oxidative stress response
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The outbreak of HCC results from the continuous cycle of parenchymal disruption and tissue regeneration sustained by inflammation, oxidative stress, fibrogenesis and hypoxia. In this scenario, mitochondria, which are extremely adaptable to external cues, play a key role as bioenergetic factories and for the regulation of liver metabolism. The loss of mitochondrial dynamics, the accumulation of damaged mitochondria and the remodeling of mitochondrial activities may lead to metabolic reprogramming of hepatocytes, characterized by the switch towards the Warburg effect, mutagenesis, epithelial–mesenchymal transition (EMT) and several strategies of tumor escape from apoptosis in order to promote the compensatory proliferation and HCC onset. The main goal of the present work will be to summarize the main aspects related to NAFLD–HCC pathophysiology driven by mitochondrial failure and the current knowledge about mitochondrial dynamics, which could lay the groundwork for the development of new therapeutic approaches to prevent and/or manage NAFLD progression towards HCC
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
