TY - JOUR
T1 - Remodeling of mitochondrial plasticity
T2 - The key switch from nafld/nash to hcc
AU - Longo, Miriam
AU - Paolini, Erika
AU - Meroni, Marica
AU - Dongiovanni, Paola
N1 - Funding Information:
Funding: The study was supported by Ricerca Corrente Fondazione IRCCS Cà Granda, Ricerca Finalizzata Ministero della Salute RF-2013-02358319 and Ricerca Finalizzata Ministero della Salute GR-2019-12370172.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/4/2
Y1 - 2021/4/2
N2 - 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.
AB - 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.
KW - Apoptosis
KW - HCC
KW - Hepatocytes
KW - HSCs
KW - KCs
KW - Metabolic reprogramming
KW - Mitochondrial dynamics
KW - NAFLD
KW - NASH
KW - Warburg effect
UR - http://www.scopus.com/inward/record.url?scp=85104310187&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104310187&partnerID=8YFLogxK
U2 - 10.3390/ijms22084173
DO - 10.3390/ijms22084173
M3 - Review article
C2 - 33920670
AN - SCOPUS:85104310187
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 8
M1 - 4173
ER -