Abstract
As the main metabolic and detoxification organ, the liver constantly adapts its activity to fulfill the energy requirements of the whole body. Despite the remarkable adaptive capacity of the liver, prolonged exposure to noxious stimuli such as alcohol, viruses and metabolic disorders results in the development of chronic liver disease that can progress to hepatocellular carcinoma (HCC), which is currently the second leading cause of cancer-related death worldwide. Metabolic rewiring is a common feature of cancers, including HCC. Altered mito-nuclear communication is emerging as a driving force in the metabolic reprogramming of cancer cells, affecting all aspects of cancer biology from neoplastic transformation to acquired drug resistance. Here, we explore relevant aspects (and discuss recent findings) of mito-nuclear crosstalk in the metabolic reprogramming of hepatocellular carcinoma.
Highlights
A tumor is a very harsh environment to live in
“aerobic glycolysis” was due to defective mitochondria respiration that forces cancer cells to rely on an alternative pathway for energy production [3]; it is clear that mitochondria are not dysfunctional in cancer cells
This review summarizes the recent advances in relevant aspects of the mitochondrial-nuclear communication, in the context of the metabolic reprogramming of hepatocellular carcinoma
Summary
A tumor is a very harsh environment to live in. Poor oxygenation, low nutrient levels, high concentration of waste metabolites, and acidic pH are inevitable consequences of a crowded and disorganized mass of fast-growing cells. The ETC complex assembly, requires a regulation of both nuclear-encoded and mitochondrial-encoded subunits, which need to be in proper stoichiometric ratios Failure to maintain this proportion leads to the mito-nuclear protein imbalance, which could result in reduced mitochondrial respiration and ATP synthesis [6]. Mitohormesis is a clear paradigm of the importance of mito-nuclear communications, since the stress-induced signaling originating from mitochondria elicit a nuclear response aimed at increasing the antioxidant defenses, to promote the mitochondrial turnover through mitophagy and biogenesis, and to remodel mitochondrial metabolism. A transient increase in mitochondrial oxidative stress during fetal development triggers a stable hormetic response in the adult liver that heightens the basal level of mitochondrial antioxidant defense This mitohormetic adaptive response requires the activation of nuclear respiratory factor (NRF2), peroxisome proliferator-activated receptors (PPARs) and the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α) pathways [9]. This review summarizes the recent advances in relevant aspects of the mitochondrial-nuclear communication, in the context of the metabolic reprogramming of hepatocellular carcinoma
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