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.

IntroductionAlcohol misuse is the most common form of substance misuse and is associated with liver, cardiovascular, and metabolic diseases as well as with infections and cancers.1 Although an estimated 20% to 25% of people who drink heavily develop alcohol-related liver disease,2 40% to 60% of people with alcohol misuse have alcohol-related myopathy.3 Evidence that alcohol use leads to skeletal muscle (SKM) weakness, even in the absence of neuropathology, was independently documented in the 1800s by James Jackson4 and Magnus Huss.5

At-risk alcohol use is associated with multisystemic effects and end-organ injury, and significantly contributes to global health burden. Several alcohol-mediated mechanisms have been identified, with bioenergetic maladaptation gaining credence as an underlying pathophysiological mechanism contributing to cellular injury. This evidence-based review focuses on the current knowledge of alcohol-induced bioenergetic adaptations in metabolically active tissues: liver, cardiac and skeletal muscle, pancreas, and brain. Alcohol metabolism itself significantly interferes with bioenergetic pathways in tissues, particularly the liver. Alcohol decreases states of respiration in the electron transport chain, and activity and expression of respiratory complexes, with a net effect to decrease ATP content. In addition, alcohol dysregulates major metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and fatty acid oxidation. These bioenergetic alterations are influenced by alcohol-mediated changes in mitochondrial morphology, biogenesis, and dynamics. The review highlights similarities and differences in bioenergetic adaptations according to tissue type, pattern of (acute vs. chronic) alcohol use, and energy substrate availability. The compromised bioenergetics synergizes with other critical pathophysiological mechanisms, including increased oxidative stress and accelerates cellular dysfunction, promoting senescence, programmed cell death, and end-organ injury.

Chronic excessive alcohol use is a well-recognized risk factor for pancreatic dysfunction and pancreatitis development. Evidence from in vivo and in vitro studies indicates that the detrimental effects of alcohol on the pancreas are from the direct toxic effects of metabolites and byproducts of ethanol metabolism such as reactive oxygen species. Pancreatic dysfunction and pancreatitis development are now increasingly thought to be multifactorial conditions, where alcohol, genetics, lifestyle, and infectious agents may determine the initiation and course of the disease. In this review, we first highlight the role of nonoxidative ethanol metabolism in the generation and accumulation of fatty acid ethyl esters (FAEEs) that cause multi-organellar dysfunction in the pancreas which ultimately leads to pancreatitis development. Further, we discuss how alcohol-mediated altered autophagy leads to the development of pancreatitis. We also provide insights into how alcohol interactions with other co-morbidities such as smoking or viral infections may negatively affect exocrine and endocrine pancreatic function. Finally, we present potential strategies to ameliorate organellar dysfunction which could attenuate pancreatic dysfunction and pancreatitis severity.

Work from our group demonstrated that chronic binge alcohol (CBA)-induces mitochondrial gene dysregulation at end-stage disease of simian immunodeficiency virus (SIV) infection in antiretroviral therapy (ART) naïve rhesus macaques. Alterations in gene expression can disrupt mitochondrial homeostasis and in turn contribute to the risk of metabolic comorbidities characterized by loss of skeletal muscle (SKM) functional mass that are associated with CBA, human immunodeficiency virus (HIV) infection, and prolonged ART. The aim of this study was to examine the interaction of CBA and ART on SKM fiber oxidative capacity and myoblast mitochondrial respiration in asymptomatic SIV-infected macaques. SKM biopsies were obtained and myoblasts isolated at baseline and 11 months post-SIV infection from CBA/SIV/ART+ and from sucrose (SUC)-treated SIV-infected (SUC/SIV/ART+) macaques. CBA and ART decreased succinate dehydrogenase (SDH) activity in type 1 and type 2b fibers as determined by immunohistochemistry. Myoblasts isolated from CBA/SIV/ART+ macaques showed decreased maximal oxygen consumption rate (OCR) compared to myoblasts from control macaques. Maximal OCR was significantly increased in control myoblasts following incubation with formoterol, a beta adrenergic agonist, and this was associated with increased PGC-1α expression and mtDNA quantity. Additionally, formoterol treatment of myoblasts isolated from CBA/SIV/ART+ macaques partially restored maximal OCR to levels not significantly different from control. These results show that CBA in combination with ART impairs myoblast mitochondrial homeostasis in SIV-infected macaques. Moreover, our findings suggest that adrenergic agonists can potentially ameliorate mitochondrial dysfunction. Future studies will elucidate whether physical exercise in HIV patients with alcohol use disorder can improve mitochondrial health.