Mitochondrial dysfunction and alcohol-associated liver disease: a novel pathway and therapeutic target

Abstract

In a recent study in signal transduction and targeted therapy, Zhou et al. provided novel experimental data on the role of DNAdependent protein kinase catalytic subunit (DNA-PKcs) in causing abnormalities in the structure and function of mitochondria of hepatocytes, leading to liver injury and alcohol-associated liver disease (ALD). 1 Mitochondria play a crucial role in cellular energy metabolism and in reactive species formation. 2 Several studies in both animal and human models have demonstrated that alcohol intake alters mitochondrial morphology and function by causing impairment of mitochondrial biogenesis, mitochondrial DNA damage, lipid accumulation, oxidative stress, and hepatocellular apoptosis. 2,3 Therefore, identification of the mechanisms through which alcohol induces mitochondrial dysfunction and liver injury is vital for understanding of the pathogenesis of ALD.Mitochondrial fission and mitophagy are important processes for maintaining mitochondrial homeostasis. 4 In a study conducted by the same group, impairment of mitochondrial fission and mitophagy through upregulation of nuclear receptor subfamily 4 group A member 1 (NR4A1) and subsequent activation of the DNA-PKcs/p53 pathway resulted in mitochondrial dysfunction, with reduction in mitochondrial potential, oxidative stress, calcium overload, mitochondrial respiratory collapse, and ATP deficiency. NR4A1 gene encodes the steroid-thyroid hormone-retinoid receptor superfamily, and the encoded protein acts as transcription factor. Genetic deletion of NR4A1 or DNA-PKcs reversed mitochondrial dysfunction and prevented diet-induced nonalcoholic fatty liver disease. 5 The role of NR4A1/DNA-PKcs/P53 pathway in the regulation of mitochondrial fission and mitophagy, however, has not been studied in ALD.In this issue of signal transduction and targeted therapy, Zhou et al. demonstrate the role of DNA-PKcs in the pathogenesis of ALD. In ethanol-fed mice, DNA-PKcs was significantly upregulated and activated in comparison with controls. The activation of DNA-PKcs was associated with the development of severe ALD in wildtype (WT) mice treated with alcohol, with hepatocyte vacuolation, fibrosis, steatosis, increased lipid droplets, and elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and AST/ALT ratio. These findings were absent in liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice treated with alcohol. In addition, transcription of inflammation/fibrosis markers, such as monocyte chemotactic protein 1, macrophage inflammatory protein 1α, interleukin 8, and increased mitochondrial apoptosisrelated proteins were seen in WT mice treated with alcohol, but not in DNA-PKcs knockout mice treated with alcohol. Other markers for mitochondrial dysfunction, such as oxidative stress, impaired mitochondrial biogenesis, and distorted morphology were also detected in alcohol-treated WT mice but not in DNA-PKcs knockout mice.Alcohol-induced mitochondrial fission characterized by formation of small, round fragmented mitochondria was mediated...

Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis

“…Lastly, maladaptive changes in liver metabolism were also identified in this study, including a reduction in CL synthesis enzymes and CL levels in AC and AH. In addition to enhanced CL oxidation, 52 a reduction in CL synthesis could compromise mitochondrial function 33 (eg, mt biogenesis), leading to alterations in liver function, including regeneration. 35 Although this study is unique in many ways, the approach had several limitations, including study cohorts being primarily comprised of men, limiting the ability to evaluate sex differences.…”

“…Hepatic mitochondrial dysfunction is a hallmark of ALD. 33 Our analysis identified that among the proteins down-regulated in AH was a subset involved in the synthesis of cardiolipin (CL) (Table 2), a phospholipid that maintains mitochondria bioenergetics 34 during hepatocyte proliferation and liver regeneration. 35 Figure 7A summarizes the CL biosynthesis pathway and shows the primarily negative correlation between MELD score and enzymes in this pathway, including critical proteins 1acylglycerol-3-phosphate O-acyltransferase 2 (PLCB), protein tyrosine phosphatase mitochondrial 1 (PTPMT1), and hydroxyacyl-CoA dehydrogenase trifunctional complex subunit alpha (ECHA).…”

New Therapeutic Options for Advanced Hepatocellular Carcinoma

“…41,42 Thalidomide can inhibit angiogenesis by interfering with the effect of VEGF and fibroblast growth factor. 43 Several clinical trials discussed the therapeutic effect of thalidomide on patients with HCC whose cancer could not be resected or treated locally. 44 It was found that the objective response rate of thalidomide was about 5%, and 10% to 30% of patients demonstrated disease stability for 2 months after thalidomide single drug treatment.…”

Alcohol Impairs Immunometabolism and Promotes Naïve T Cell Differentiation to Pro-Inflammatory Th1 CD4+ T Cells

“…Mitochondria play a crucial role in cellular energy metabolism and Treg differentiation ( 29 , 32 ). Both preclinical and clinical studies have demonstrated that ethanol alters mitochondrial function by impairing mitochondrial biogenesis, increasing mitochondrial DNA damage, and increasing oxidative stress ( 38 – 40 ). Further, ethanol dysregulates gene expression implicated in mitohormesis, a response to stress to restore health and viability of mitochondria, and induces mitochondrial DNA (mtDNA) damage within alveolar macrophages ( 41 , 42 ).…”