Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury

Abstract

Alcohol misuse, directly or indirectly as a result of its metabolism, negatively impacts most tissues, including four with critical roles in energy metabolism regulation: the liver, pancreas, adipose, and skeletal muscle. Mitochondria have long been studied for their biosynthetic roles, such as ATP synthesis and initiation of apoptosis. However, current research has provided evidence that mitochondria participate in myriad cellular processes, including immune activation, nutrient sensing in pancreatic β-cells, and skeletal muscle stem and progenitor cell differentiation. The literature indicates that alcohol impairs mitochondrial respiratory capacity, promoting reactive oxygen species (ROS) generation and disrupting mitochondrial dynamics, leading to dysfunctional mitochondria accumulation. As discussed in this review, mitochondrial dyshomeostasis emerges at a nexus between alcohol-disrupted cellular energy metabolism and tissue injury. Here, we highlight this link and focus on alcohol-mediated disruption of immunometabolism, which refers to two distinct, yet interrelated processes. Extrinsic immunometabolism involves processes whereby immune cells and their products influence cellular and/or tissue metabolism. Intrinsic immunometabolism describes immune cell fuel utilization and bioenergetics that affect intracellular processes. Alcohol-induced mitochondrial dysregulation negatively impacts immunometabolism in immune cells, contributing to tissue injury. This review will present the current state of literature, describing alcohol-mediated metabolic and immunometabolic dysregulation from a mitochondrial perspective.

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction

“…Mitochondria are critical sites of bioenergetics, fat oxidation, intermediary metabolism, apoptosis, mitophagy, and redox homeostasis [ 90 – 93 ]. They are one of the primary sources of oxidative stress involved in fatty liver diseases [ 94 ]; α-ketoglutarate dehydrogenase and pyruvate dehydrogenase are involved in redox reactions to generate NADH and FADH 2 in the tricarboxylic acid (TCA) cycle [ 95 ], then in the electron transport chain (ETC), complexes I, II, and III perform redox reactions to generate ATP [ 18 ]. Thus, to balance out the ROS/RNS generated from these redox reactions, many mitochondrial antioxidants and enzymes exist.…”

“…Typically, in the second line of defense, mitochondria trigger mitophagy to restore redox homeostasis and retain the function of other mitochondria and organelles for cellular activities [ 101 ]. However, these natural lines of defense in mitochondria can be altered after excessive consumption of or exposure to alcohol (ethanol) [ 85 , 94 ], drugs [ 66 , 102 , 103 ], viruses [ 104 ], and some nutrients, including fructose [ 105 ]. Specifically, these exposures can alter mitochondrial redox homeostasis and oxidatively damage DNA [ 106 , 107 ], RNA [ 106 ], lipids, and proteins, through PTMs [ 8 , 26 , 48 , 70 , 108 , 109 ], causing inactivation of their functions and signaling pathways, leading to mitochondrial dysfunction [ 26 , 53 , 68 , 83 ], death of hepatocytes, and liver damage [ 17 , 110 ] or age-related conditions [ 91 , 111 – 113 ].…”

Repurposing Niclosamide as a Therapeutic Drug against Acute Liver Failure by Suppressing Ferroptosis

“…The liver plays a crucial role in maintaining immune tolerance to self-antigens while effectively responding to pathogenic challenges [ 20 ]. However, dysregulation of immune responses can lead to liver diseases, including autoimmune liver diseases and liver injury [ 21 ]. Antigen-presenting cells (APCs), particularly macrophages, assume a pivotal role in the immune response and tissue repair processes in ALF [ 22 ].…”

Astaxanthin Protects against Alcoholic Liver Injury via Regulating Mitochondrial Redox Balance and Calcium Homeostasis

“…Additionally, as the major organ involved in metabolism of alcohol, the liver contains plenty of mitochondria for energy production via oxidation of multiple substrates, thus is specifically susceptible to damage from alcohol consumption . Previous studies have shown that chronic alcohol administration was able to impair the ultrastructure and molecular dynamics of mitochondria, as well as the activity of respiratory chain complexes and synthesis of adenosine 5′-triphosphate (ATP) . Meanwhile, the mitochondrial oxidative phosphorylation (OXPHOS) was also interfered by alcohol via inhibiting the synthesis of proteins of the electron transport chain and the ATP synthase .…”

“…5 Previous studies have shown that chronic alcohol administration was able to impair the ultrastructure and molecular dynamics of mitochondria, as well as the activity of respiratory chain complexes and synthesis of adenosine 5′-triphosphate (ATP). 6 Meanwhile, the mitochondrial oxidative phosphorylation (OXPHOS) was also interfered by alcohol via inhibiting the synthesis of proteins of the electron transport chain and the ATP synthase. 7 Conversely, mitochondrial damage of the liver will be doomed to energy dysbolism and enhances ROS formation.…”