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.

Keywords: HCC; HSCs; KCs; NAFLD; NASH; Warburg effect; apoptosis; hepatocytes; metabolic reprogramming; mitochondrial dynamics.

Figure 1

The prominent role of mitochondria in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Sedentary lifestyle coupled to hypercaloric diet and genetic background lead to the development of insulin resistance (IR), which causes NAFLD onset. In addition, compensatory hyperinsulinemia activates de novo lipogenesis (DNL) and exacerbates hepatocytic fat accumulation. From the early stages of NAFLD, mitochondria adapt in number and function in response to lipid overload, increasing β-oxidation, oxidative phosphorylation (OXPHOS) capacity and biomass (mitochondrial adaptability). Nevertheless, mitochondrial flexibility is compromised during fatty liver progression towards NASH, resulting in blunted ketogenesis, tricarboxylic acid cycle (TCA), OXPHOS and adenosine triphosphate (ATP) production. Consequently, mitochondrial oxidative stress and the release of mitochondrial danger signals worsen inflammation by recruiting and activating Kupffer cells (KCs) alongside fibrogenesis through hepatic stellate cells (HSCs) activation. The inflammatory response together with enhancing apoptosis and hypoxia contribute to generating the surrounding microenvironment that influences malignant transformation and tumor escaping mechanisms. Thus, 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.

Figure 2

The landscape of HCC microenvironment in NAFLD/NASH. Over NAFLD progression, ER/oxidative stress, loss of mitochondrial adaptability and mitochondrial failure activate hepatocellular apoptotic and inflammatory pathways. Hepatocytes release mitochondrial damage-associated molecular patterns (mito-DAMPs) derived from damaged mitochondria. Mito-DAMPs bind pattern-recognition receptors (PRRs) on the Kupffer cells’ (KCs) and HSCs’ surface, exacerbating tissue inflammation and fibrosis. In addition, HSCs’ activation may also be stimulated by pro-inflammatory cytokines released from both hepatocytes and KCs. In turn, KCs enhance pro-proliferative signals (i.e., IL-6), thus triggering the compensatory proliferation of hepatocytes, a possible mechanism to avoid apoptosis. The continuous exposure to inflammation, fibrosis, and apoptotic signals worsens hepatic oxygen distribution (hypoxia). Hypoxia together with increased Ca²⁺ efflux, derived from the disruption of ER–mitochondrial communications, promote the growth of CSCs and the recruitment of tumor-associated macrophages (TAMs), T-regulatory cells (Treg) and dendritic cells, which suppress cytotoxic immune response and co-adjuvate hepatocarcinogenesis.

Figure 3

Mitochondrial pathways implicated in the pathogenesis of NASH-related HCC. Sedentary lifestyle, dietary habits and genetic background contribute to NAFLD development and its progression to NASH-driven HCC. The excess of hepatic fat accumulation promotes DNL, mitochondrial dysfunctions and the disruption of ER–mitochondrial contact sites. Consequently, the increased content of LDs may favor either lipotoxicity or energetic substrates for cell viability. The loss of mitochondrial flexibility and reduced mitophagy exacerbate the number of degenerated mitochondria, which produce ROS and release cytochrome C and AIF, thus activating apoptosis. The oxidative stress overwhelms antioxidant defenses, affects OXPHOS capacity, and triggers inflammatory signals (tumorigenic cytokines). In addition, ROS induce the mutagenesis of both nuclear DNA and mtDNA, causing the aberrant activation of proliferative pathways and the delivery of mito-DAMPs, respectively. Mito-Damps, including mitochondrial formyl-peptides and mtDNA fragments, could activate PRR receptors on the hepatocellular surface, KCs and HSCs, prompting inflammation and fibrosis. ROS-induced pro-survival signaling (i.e., JAK/STAT, ERK, MAPK) is able to counteract cell death by inducing the degradation of onco-suppressors and expanding the amount of hepatic progenitor cells. Moreover, the interruption of ER–mitochondria communication raises the efflux of cytosolic Ca²⁺, further contributing to ROS production and mutagenesis. Finally, hepatocytes undergo metabolic reprogramming, characterized by enhanced glucose uptake, high rates of glycolysis, and lactate production, which is rapidly secreted to avoid cytosolic acidification. Overall, a lipid-rich microenviroment combined with early loss of mitochondrial adaptability, both hallmarks of NAFLD onset and progression, may rearrange hepatocellular metabolism and the interplay between hepatocytes and non-parenchymal cells in order to overcome an adverse environment and trigger tumorigenesis.