Mini Reviews in Medicinal Chemistry - Volume 15, Issue 5, 2015

Bipolar disorder is a common, chronic, and complex mental illness. Bipolar disorder is frequently comorbid with primary mitochondrial and metabolic disorders, and studies have implicated mitochondrial dysfunction in its pathophysiology. In the brains of people with bipolar disorder, high-energy phosphates are decreased, lactate is elevated and pH decreased, which together suggest a shift toward glycolysis for energy production. Furthermore, oxidative stress is increased, and calcium signalling dysregulated. Additionally there is downregulation of the expression of mitochondrial complexes, especially complex I. The therapeutic effects of some bipolar disorder drugs have recently been shown to be related to these mechanisms. In this review we will evaluate current research on the interactions between mitochondrial dysfunction and bipolar disorder pathology. We will then appraise the current literature describing the effects of bipolar disorder drugs on mitochondrial function, and discuss ramifications for future research.

The translocator protein 18 kDa (TSPO) is localized in the outer mitochondrial membrane of many cell types and its expression is found to be up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions, and neurological diseases, e.g. amyotrophic lateral sclerosis (ALS). Its primary function is to mediate the transport of cholesterol into the inner compartments of mitochondria. Moreover, TSPO is interacting and building up functional complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC), the adenine nucleotide transporter (ANT), hexokinase I and II and Glycogen synthase kinase 3 beta (GSK3β). This mini review will focus on the role of TSPO as a central regulator of mitochondrial function with regard to pathologic states and as a target for new therapeutic strategies for the treatment of psychiatric disorders.

Mitochondria are organelles that play a central role in processes related to cellular viability, such as energy production, cell growth, cell death via apoptosis, and metabolism of reactive oxygen species (ROS). We can observe behavioral abnormalities relevant to autism spectrum disorders (ASDs) and their recovery mediated by the mTOR inhibitor rapamycin in mouse models. In Tsc2+/- mice, the transcription of multiple genes involved in mTOR signaling is enhanced, suggesting a crucial role of dysregulated mTOR signaling in the ASD model. This review proposes that the mTOR inhibitor may be useful for the pharmacological treatment of ASD. This review offers novel insights into mitochondrial dysfunction and the related impaired glutathione synthesis and lower detoxification capacity. Firstly, children with ASD and concomitant mitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders, and it therefore shows that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction are likely due to these mitochondrial disorders. Secondly, the adenosine triphosphate (ATP) production/oxygen consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress, and disruption of ATP synthesis alone may be related to impaired glutathione synthesis. Finally, a decrease in total antioxidant capacity may account for ASD children who show core social and behavioral impairments without neurological and somatic symptoms.

The development and function of neuronal synapses are orchestrated by various extrinsic factors through intracellular signaling cascades that often involve protein kinases. One important kinase at the synapse is the proline-directed serine/ threonine kinase Cdk5. Although early pharmacological and genetic studies have pointed out the critical role of Cdk5 in regulating synapse function, the precise mechanisms have only been unraveled in recent years through the identification and characterization of multiple substrates. Emerging studies also indicate that Cdk5 dysregulation is linked to mitochondrial dysfunction. This review focuses on recent progress in our understanding of the multiple roles of Cdk5 in mitochondrial function, synapse development and plasticity through phosphorylation of specific substrates at different cellular compartments.

The mitochondrial carnitine/acylcarnitine translocase has been identified, purified and reconstituted in liposomes in 1990. Since that time it has been object of studies aimed to characterize its function and to define the molecular determinants of the translocation pathway. Thanks to these tenacious studies the molecular map of the amino acids involved in the catalysis has been constructed and the roles of critical residues in the translocation pathway have been elucidated. This has been possible through the combination of transport assay in reconstituted liposomes, site-directed mutagenesis, chemical labeling and bioinformatics. Recently some molecules which modulate CACT activity have been identified, such as glutathione and hydrogen peroxide, constituting some of the few cases of control mechanisms of mitochondrial carriers. The vast knowledge on the carnitine/acylcarnitine translocase is essential both as a progress in basic science and as instrument to foresee therapeutic or toxic effects of xenobiotics and drugs. Such studies have been already started pointing out the inhibitory action of drugs such as K+/H+-ATPase inhibitors (omeprazole) or antibiotics (β-lactams) on the carnitine/acylcarnitine translocase, which can explain some of their adverse effects.

Advances in the use of organotin(IV) compounds have gained relevant interest in both the chemical and pharmaceutical industry. Tin(IV) form stable complexes with a unique structure and physicochemical properties that are used in organic synthesis as heat stabilizers and catalysts, in drug development as biologically active agents, and in other areas. This review focuses on recent progress in the classical and convenient synthesis procedure, on their mechanism of action, and biological activities as antitumoral and antimicrobial agents.

Estradiol (E2) is a steroid hormone whose physiological actions are mainly mediated by its interaction with intracellular estrogen receptors (ER) leading to modification on the mRNA and protein synthesis in its target cells. However, estrogens can also activate several intracellular signal transduction cascades by non-genomic mechanisms. Estrogens must be inactivated and removed from blood through its conversion to soluble compounds with an apparent low estrogenic activity and decreased affinity for ER. In this context, 2-methoxyestradiol (2ME2) is generated by a sequential hydroxylation of E2 via the enzyme cytochrome P450 isoform 1A1 to produce 2-hydroxyestradiol (2OHE2) followed by a conjugation reaction catalyzed by the enzyme Catechol-O-Methyltransferase generating 2ME2 from 2OHE2. Recent evidence indicates that physiological concentration of 2ME2 may regulate several biological processes while high concentrations of this metabolite may induce pathophysiological alterations in several tissues. In the last years, 2ME2 has also been described as a promising anticancer drug although its cellular and molecular mechanisms are still being disclosed. Herein, we will review the available literature concerning the role of 2ME2 in health and disease. We will focus on to describing the intracellular mechanisms by which 2ME2 exerts its effects on reproductive and non-reproductive tissues. The promising anticancer effects of 2ME2 and its synthetic derivatives will also be discussed. Finally, a group of 2ME2-target genes that could be used as biomarkers of 2ME2 under physiological or pathophysiological conditions will be reviewed.