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.

Effects of tobacco smoke on hematologic derangements have received little attention. This study employed a mouse model of cigarette smoke exposure to explore the effects on bone marrow niche function. While lung cancer is the most widely studied consequence of tobacco smoke exposure, other malignancies, including leukemia, are associated with tobacco smoke exposure. Animals received cigarette smoke exposure for 6 h/day, 5 days/week for 9 months. Results reveal that the hematopoietic stem and progenitor cell (HSPC) pool size is reduced by cigarette smoke exposure. We next examined the effect of cigarette smoke exposure on one supporting cell type of the niche, the mesenchymal stromal cells (MSCs). Smoke exposure decreased the number of MSCs. Transplantation of naïve HSPCs into irradiated mice with cigarette smoke exposure yielded fewer numbers of engrafted HSPCs. This result suggests that smoke-exposed mice possess dysfunctional niches, resulting in abnormal hematopoiesis. Co-culture experiments using MSCs isolated from control or cigarette smoke-exposed mice with naïve HSPCs in vitro showed that MSCs from cigarette smoke-exposed mice generated marked expansion of naïve HSPCs. These data show that cigarette smoke exposure decreases in vivo MSC and HSC number and also increases pro-proliferative gene expression by cigarette smoke-exposed MSCs, which may stimulate HSPC expansion. These results of this investigation are clinically relevant to both bone marrow donors with a history of smoking and bone marrow transplant (BMT) recipients with a history of smoking.

Alcohol exerts significant immunomodulatory effects on innate and adaptive immune responses, impairing host defense against infections. Gut-mucosa-derived dendritic cells (DCs) traffic to mesenteric lymph nodes (MLNs) through mesenteric lymphatic vessels (MLVs), contributing to intestinal antigen homeostasis. Previously, we demonstrated that acute alcohol administration to male rats induces MLV hyperpermeability resulting in perilymphatic adipose tissue (PLAT) inflammation and insulin signaling dysregulation. We hypothesized that alcohol-induced MLV hyperpermeability can lead to DC leakage to PLAT. DCs promote adipose tissue regulatory T cell (Treg) expansion, and this has been proposed as a mechanism underlying age-associated insulin resistance (IR). The aim of this study was to determine whether chronic alcohol consumption promotes DC leakage to PLAT and results in metabolic dysregulation. Male rats received a Lieber–DeCarli liquid diet containing 36% of calories from alcohol for 10 weeks. Time-matched control animals were pair-fed. PLAT, MLNs, and peripheral blood leukocytes (PBLs) were isolated for flow cytometry analyses. PLAT explants were used for determinations of insulin-induced glucose uptake. Chronic alcohol consumption decreased MLN CD4/CD8 ratio and Treg frequency in PBLs. Alcohol increased the frequency of DCs, CD4 T cells, and Tregs in PLAT. Lastly, alcohol decreased insulin-stimulated glucose uptake in PLAT. Collectively, these findings suggest that alcohol-induced immune cell deviation from the gut–MLN pathway is associated with PLAT immunometabolic dysregulation. Whether this immune cell deviation impacts induction of mucosal immunity warrants further investigation.

Effective antiretroviral therapy (ART) has transitioned HIV to a chronic disease, with more than 50% of people living with HIV (PLWH) being over the age of 50. HIV targets activated CD4⁺ T cells expressing HIV-specific co-receptors (CCR5 and CXCR4). Previously, we reported that chronic binge alcohol (CBA)-administered male rhesus macaques had a higher percentage of gut CD4⁺ T cells expressing simian immunodeficiency virus (SIV) co-receptor CXCR4. Evidence also suggests that gonadal hormone loss increased activated peripheral T cells. Further, mitochondrial function is critical for HIV replication and alcohol dysregulates mitochondrial homeostasis. Hence, we tested the hypothesis that CBA and ovariectomy (OVX) increase circulating activated CD4⁺ T cells expressing SIV co-receptors and dysregulate mitochondrial homeostasis in SIV-infected female rhesus macaques. Results showed that at the study end-point, CBA/SHAM animals had increased peripheral CD4⁺ T cell SIV co-receptor expression, and a lower CD4⁺ T cell count compared to CBA/OVX animals. CBA and OVX animals had altered peripheral immune cell gene expression important for maintaining mitochondrial homeostasis. These results provide insights into how at-risk alcohol use could potentially impact viral expression in cellular reservoirs, particularly in SIV-infected ovariectomized rhesus macaques.