Remodeling of mitochondrial plasticity: The key switch from nafld/nash to hcc

Miriam Longo, Erika Paolini, Marica Meroni, Paola Dongiovanni

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Article number4173
JournalInternational Journal of Molecular Sciences
Issue number8
Publication statusPublished - Apr 2 2021


  • Apoptosis
  • HCC
  • Hepatocytes
  • HSCs
  • KCs
  • Metabolic reprogramming
  • Mitochondrial dynamics
  • NASH
  • Warburg effect

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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