Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Version 1 : Received: 26 March 2021 / Approved: 30 March 2021 / Online: 30 March 2021 (09:29:34 CEST)

A peer-reviewed article of this Preprint also exists.

Journal reference: International Journal of Molecular Sciences 2021
DOI: 10.3390/ijms22084173

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 which may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlighted that mitochondrial dysfunction due to loss of mitochondrial flexibility, may arise before overt NAFLD and since the early stages of liver injury. Mitochondrial failure not only promotes 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 remodeling of glucidic-lipidic metabolism combined to 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 purposes and for development of potential preventive or curative strategies.

Keywords

NAFLD; NASH; HCC; mitochondrial dynamics; hepatocytes; KCs, HSCs; apoptosis; metabolic reprogramming; Warburg effect

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