👤 Y Liu

Uncoupling proteins (UCPs) belong to a large family of mitochondrial solute carriers 25 (SLC25s) localized at the inner mitochondrial membrane. UCPs transport protons directly from the intermembrane space to the matrix. Of five structural homologues (UCP1 to 5), UCP4 and 5 are principally expressed in the central nervous system (CNS). Neurons derived their energy in the form of ATP that is generated through oxidative phosphorylation carried out by five multiprotein complexes (Complexes I-V) embedded in the inner mitochondrial membrane. In oxidative phosphorylation, the flow of electrons generated by the oxidation of substrates through the electron transport chain to molecular oxygen at Complex IV leads to the transport of protons from the matrix to the intermembrane space by Complex I, III, and IV. This movement of protons to the intermembrane space generates a proton gradient (mitochondrial membrane potential; MMP) across the inner membrane. Complex V (ATP synthase) uses this MMP to drive the conversion of ADP to ATP. Some electrons escape to oxygen-forming harmful reactive oxygen species (ROS). Proton leakage back to the matrix which bypasses Complex V resulting in a major reduction in ROS formation while having a minimal effect on MMP and hence, ATP synthesis; a process termed "mild uncoupling." UCPs act to promote this proton leakage as means to prevent excessive build up of MMP and ROS formation. In this review, we discuss the structure and function of mitochondrial UCPs 4 and 5 and factors influencing their expression. Hypotheses concerning the evolution of the two proteins are examined. The protective mechanisms of the two proteins against neurotoxins and their possible role in regulating intracellular calcium movement, particularly with regard to the pathogenesis of Parkinson's disease are discussed. Show less

Mitochondrial uncoupling protein-4 (UCP4) protects against Complex I deficiency as induced by 1-methyl-4-phenylpyridinium (MPP+), but how UCP4 affects mitochondrial function is unclear. Here we investigated how UCP4 affects mitochondrial bioenergetics in SH-SY5Y cells. Cells stably overexpressing UCP4 exhibited higher oxygen consumption (10.1%, p<0.01), with 20% greater proton leak than vector controls (p<0.01). Increased ATP supply was observed in UCP4-overexpressing cells compared to controls (p<0.05). Although state 4 and state 3 respiration rates of UCP4-overexpressing and control cells were similar, Complex II activity in UCP4-overexpressing cells was 30% higher (p<0.05), associated with protein binding between UCP4 and Complex II, but not that of either Complex I or IV. Mitochondrial ADP consumption by succinate-induced respiration was 26% higher in UCP4-overexpressing cells, with 20% higher ADP:O ratio (p<0.05). ADP/ATP exchange rate was not altered by UCP4 overexpression, as shown by unchanged mitochondrial ADP uptake activity. UCP4 overexpression retained normal mitochondrial morphology in situ, with similar mitochondrial membrane potential compared to controls. Our findings elucidate how UCP4 overexpression increases ATP synthesis by specifically interacting with Complex II. This highlights a unique role of UCP4 as a potential regulatory target to modulate mitochondrial Complex II and ATP output in preserving existing neurons against energy crisis. Show less

In this chapter several aspects of Pt(II) are highlighted that focus on the properties of Pt(II)-RNA adducts and the possibility that they influence RNA-based processes in cells. Cellular distribution of Pt(II) complexes results in significant platination of RNA, and localization studies find Pt(II) in the nucleus, nucleolus, and a distribution of other sites in cells. Treatment with Pt(II) compounds disrupts RNA-based processes including enzymatic processing, splicing, and translation, and this disruption may be indicative of structural changes to RNA or RNA-protein complexes. Several RNA-Pt(II) adducts have been characterized in vitro by biochemical and other methods. Evidence for Pt(II) binding in non-helical regions and for Pt(II) cross-linking of internal loops has been found. Although platinated sites have been identified, there currently exists very little in the way of detailed structural characterization of RNA-Pt(II) adducts. Some insight into the details of Pt(II) coordination to RNA, especially RNA helices, can be gained from DNA model systems. Many RNA structures, however, contain complex tertiary folds and common, purine-rich structural elements that present suitable Pt(II) nucleophiles in unique arrangements which may hold the potential for novel types of platinum-RNA adducts. Future research aimed at structural characterization of platinum-RNA adducts may provide further insights into platinum-nucleic acid binding motifs, and perhaps provide a rationale for the observed inhibition by Pt(II) complexes of splicing, translation, and enzymatic processing. Show less

The condensation of DNA is essential for biological processes such as DNA transcription and replication, and its study receives additional impetus from an interest in gene therapy. Although many efficacious condensing agents have been discovered and investigated, little is known about the conversation of condensation-release under suitable conditions. A novel class of DNA condensing agents based on small azaheterocyclic metal-binding molecules has been discovered and described. Both linear and plasmid DNA can be condensed to nanoparticles by the title compounds with 50 °C incubation, especially in the presence of divalent metal ions. Importantly, this condensation may be released to original forms with little or no damage to the DNA under incubation at physiological temperatures. These changes in DNA morphology over time have been analyzed by gel electrophoresis, circular dichroism (CD), and atomic force microscopy (AFM). The present work might help to develop strategies for the design and synthesis of controllable condensing agents, which may also be applied to control gene expression and delivery. Show less

The XPD helicase (Rad3 in Saccharomyces cerevisiae) is a component of transcription factor IIH (TFIIH), which functions in transcription initiation and Nucleotide Excision Repair in eukaryotes, catalyzing DNA duplex opening localized to the transcription start site or site of DNA damage, respectively. XPD has a 5' to 3' polarity and the helicase activity is dependent on an iron-sulfur cluster binding domain, a feature that is conserved in related helicases such as FancJ. The xpd gene is the target of mutation in patients with xeroderma pigmentosum, trichothiodystrophy, and Cockayne's syndrome, characterized by a wide spectrum of symptoms ranging from cancer susceptibility to neurological and developmental defects. The 2.25 A crystal structure of XPD from the crenarchaeon Sulfolobus tokodaii, presented here together with detailed biochemical analyses, allows a molecular understanding of the structural basis for helicase activity and explains the phenotypes of xpd mutations in humans. Show less

AIM: To investigate the aquation of oxaliplatin in aqueous solution at different temperatures and gain the kinetic data. METHODS: Electronic conductometry and high performance liquid chromatography (HPLC) were used to measure the oxaliplatin content in the reaction systems at different time. RESULTS: The aquation of oxaliplatin followed a pseudo-first-order rate law. In the absence of H+, the observed rate constant kobs was 7.76 x 10(-6).min-1 and the half life t1/2 was 62 days at 25 degrees C. In the presence of H+, the aquation could be accelerated by H+ according to the equation kobs = (2.61 + 21.9 [H+]) x 10(-4).min-1. The mechanism of aquation has also been proposed in this paper. From the mechanism, the rate of aquation following to r = (k1 k2) [l-OHP]/k-1 in the absence of H+ and r = (k1 + K0k3 [H+]) [l-OHP] in the presence of H+ have been deduced, which were in perfect agreement with the experimental results. CONCLUSION: In the absence of H+, the aqueous solution of oxaliplatin is stable, which meets to the request of clinical. Show less