Alcohol abuse and dependence in humans causes an extreme shift in metabolism for which the human brain is not evolutionarily prepared. Oxidation of ethanol and acetaldehyde are not regulated, making ethanol a dominating metabolic substrate that prevents the activity of enzymes from oxidizing their usual endogenous substrates. The enzymes required to oxidize ethanol across the variety of affected tissues all produce acetaldehyde which is then converted to acetate by aldehyde dehydrogenases (ALDHs). ALDHs are NAD+-dependent enzymes, and mitochondrial ALDH2 is likely the primary contributor to ethanol-derived acetaldehyde clearance in cells. Metabolism of alcohol has several adverse effects on mitochondria including increased free radical levels, hyperacetylation of mitochondrial proteins, and excessive mitochondrial fragmentation. This review discusses the role of astrocytic and neuronal mitochondria in ethanol metabolism that contributes to the acute and chronic changes in mitochondrial function and morphology, that might promote tolerance, dependence and withdrawal. We also propose potential modes of therapeutic intervention to reduce the toxicity of chronic alcohol consumption.
The MiT/TFE family of proteins are important regulators of a number of metabolic processes. One of their most important roles is activating the autophagy pathway in the setting of nutrient deprivation or buildup of toxic metabolites. Their proper and improper functioning in this role has been linked to several types of disease, including cancer and multiple forms of neurodegeneration. In this review we will briefly outline what is known about individual family members' roles in regulating autophagy across a variety of contexts.
β-caryophyllene (BCP) exhibits anti-proliferative properties in cancer cells. Here, we examine the hypothesis that BCP induces membrane remodeling. Our data show that high concentrations of BCP increase membrane permeability of human breast cells (hBrC) causing detachment and cell death. At a sub-lethal concentration of BCP, we show that BCP induces a striking upregulation of genes involved in cholesterol biosynthesis, including the gene that encodes for HMGCoA reductase (HMGCR), the rate-determining step in cholesterol biosynthesis. In addition, stearoyl-CoA desaturase (SCD) is also upregulated which would lead to the enhanced formation of monounsaturated fatty acids, specifically oleate and palmitoleate from stearoyl CoA and palmitoyl CoA, respectively. These fatty acids are major components of membrane phospholipids and cholesterol esters. Together, these data suggest that cells respond to BCP by increasing the synthesis of components found in membranes. These responses could be viewed as a repair mechanism and/or as a mechanism to mount resistance to the cytotoxic effect of BCP. Blocking HMGCR activity enhances the cytotoxicity of BCP, suggesting that BCP may provide an additional therapeutic tool in controlling breast cancer cell growth.
Upon binding to insulin, the β-subunit of insulin receptor (IR) is phosphorylated and instantly activates intracellular signaling. A defect in this process causes the development of several metabolic disorders including non-insulin-dependent diabetes, such as type 2 and gestational diabetes mellitus (GDM). Under diabetic conditions the phosphorylation of IR in placenta, but not in platelets, is impaired. Interestingly the cellular distribution of the serotonin transporter (SERT), which utilizes the insulin signaling for posttranslational modification, shows tissue-type-dependent variation: SERT function is impaired in GDM-associated placenta, but not in platelets. In order to understand the correlation between IR, SERT and their tissue-type-dependent features, we tested an association between SERT and IR and whether this association affects the phosphorylation of IR. Using various approaches, we demonstrated a physical association between the Carboxyl terminal of SERT and the β-subunit of IR. This association was found on the plasma membrane of the placenta and the platelets. Next, the contribution of the SERT-IR association to the phosphorylation of IR was analyzed in heterologous and endogenous expression systems following insulin-treatment. The in vivo impact of SERT-IR association on the phosphorylation of IR was explored in placenta and platelets of SERT gene knockout (KO) mice. The IR phosphorylation was significantly downregulated only in the placenta, but not in platelets of SERT-KO mice. These findings are supported by time course experiments, which demonstrate that the phosphorylation of IR occurs vis-a-vis IR-SERT association, and at least one of the IR binding domains is identified as the carboxyl-terminus of SERT. These findings suggest an important role for IR-SERT association in maintaining the phosphorylation of IR and regulating the insulin signaling in placenta.
