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

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.

Non-alcoholic steatohepatitis and risk of hepatocellular carcinoma

“…impaired ketogenesis and increased glycolysis while in the presence of oxygen) will increase the risk of NASH-related HCC. [ 36 ]…”

The Saga of Endocrine FGFs

“…Interestingly, mitochondrial dysfunction has been shown to arise in many cases of non-alcoholic fatty liver diseases (NAFLD) and promotes liver damage, induces inflammation and fibrosis, and produces a hostile microenvironment that promotes anti-apoptotic programs and mutations of hepatocytes, leading to NAFLD-driven malignant hepatocytes and HCC [ 102 ]. With FGF19 having a new and detailed relationship with mitochondria and its functions as previously discussed, one can assume that FGF19 may also be intricately linked to cancers [ 27 , 91 ].…”

Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

“…In conclusion, the effects of chronic liver disease stimuli on mitochondria, via disruption of hepatic lipid metabolism and oxidative stress, lead to cell death (apoptosis and necroptosis) and inflammatory responses, which together with immune responses, result in liver fibrogenesis and liver fibrosis [ 55 , 60 , 61 ]. In addition, the danger signals derived directly from hepatocyte mitochondria activate hepatic stellate cells and promote the progression of liver fibrosis [ 62 ].…”