Targeting Mitochondria: A New Promising Approach for the Treatment of Liver Diseases

Abstract

Mitochondrial dysfunction acts as a common pathogenetic mechanism in several acute and chronic liver diseases, such as Alcoholic and Non-Alcoholic Fatty Liver Disease (NAFLD), drug-induced steatohepatitis, viral hepatitis, biliary cirrhosis, hepatocellular carcinoma, ischemia/reperfusion injury and transplant rejection. In particular mitochondrial uncoupling,has been recently identified to play a determinant role in the pathogenesis of liver diseases by causing decrease of mitochondrial proton motive force and ATP depletion. Damaged mitochondria present defects in lipid homeostasis, bioenergetics impairment and overproduction of Reactive Oxygen Species (ROS), leading to lipid accumulation and oxidative stress. Dysfunctional and/or uncoupled mitochondria enhance the susceptibility of hepatocytes to cell death by necrosis, via ATP depletion, or by apoptosis, via membrane permeabilization. Thus, prevention of mitochondrial alterations promises to be an effective strategy for treatment of liver diseases. However, no therapy has proven to be absolutely effective, whereas those that are beneficial present several side effects. The present review summarizes the recent approaches in mitochondrial drug deliver systems and focuses on mitochondria-targeted molecules application in liver disease. New selective molecules and nanocarriers technology are also considered as potentially effective in the targeting of mitochondrial dysfunction in liver pathology.

A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice

“…Dietary supplementation of F1 significantly prevented the HFD-induced increase in oxidative stress. Thus, it is likely that increased ROS generation could contribute to HFD-induced liver lesions through the formation of a reactive and biologically active lipid peroxidation product such as 4-HNE and oxidative DNA damage (Trauner et al, 2010; Mantena et al, 2008; Kojima et al, 2007; Servidido et al, 2010). The observed increase in levels of 4-HNE and 8-OhdG in livers of mice fed with HFD is consistent with this view.…”

“…Oxidative stress has been implicated in apoptotic signaling in various cell types, including hepatocytes (Trauner et al, 2010; Mantena et al, 2008; Servidido et al, 2010). One possible mechanism by which oxidative stress can induce hepatocyte apoptosis in response to HFD is through stimulation of p38 MAPK and JNK signaling, resulting in the activation of the mitochondria-dependent intrinsic pathway signaling (Franco and Cidlowski, 2009).…”

Mitotherapy for Fatty Liver by Intravenous Administration of Exogenous Mitochondria in Male Mice

“…Patients with NAFLD are at high risk of developing steatohepatitis with fibrosis and cirrhosis. Experimental and clinical evidence have suggested that mitochondrial dysfunction is a major reason of developing NAFLD, since mitochondria are important determinants of cellular lipid metabolism and oxidant stress (Serviddio et al, 2010; Auger et al, 2015). Recent studies indicate that improvement of mitochondrial function by physical exercise and/or antioxidants prevents fat accumulation in patients with NAFLD (Guo et al, 2015; Salomone et al, 2016).…”

An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease

“…Sirt1 is decreased in a rat model of NAFLD [54] and Sirt1 hepatic deficiency leads to oxidative damage and insulin resistance [55]. Thus, there is a strong mechanistic link between deficiencies of proteins controlling mitochondrial biogenesis, function, and antioxidant capacity and the development of fatty liver disease, stimulating great interest in targeting these pathways for new therapeutics [56]. …”