Markus Etzkorn

Top-down control analysis of the cadmium effects on molluscan mitochondria and the mechanisms of cadmium-induced mitochondrial dysfunction

Cadmium (Cd) is a toxic metal and an important environmental pollutant that can strongly affect mitochondrial function and bioenergetics in animals. We investigated the mechanisms of Cd action on mitochondrial function of a marine mollusk (the eastern oyster Crassostrea virginica) by performing a top-down control analysis of the three major mitochondrial subsystems (substrate oxidation, proton leak, and phosphorylation). Our results showed that the substrate oxidation and proton leak subsystems are the main targets for Cd toxicity in oyster mitochondria. Exposure to 12.5 μM Cd strongly inhibited the substrate oxidation subsystem and stimulated the proton conductance across the inner mitochondrial membrane. Proton conductance was also elevated and substrate oxidation inhibited by Cd in the presence of a mitochondrially targeted antioxidant, MitoVitE, indicating that Cd effects on these subsystems were to a large extent ROS independent. Cd did not affect the kinetics of the phosphorylation system, indicating that it has negligible effects on F₁, F(O) ATP synthase and/or the adenine nucleotide transporter in oyster mitochondria. Cd exposure altered the patterns of control over mitochondrial respiration, increasing the degree of control conferred by the substrate oxidation subsystem, especially in resting (state 4) mitochondria. Taken together, these data suggest that Cd-induced decrease of mitochondrial efficiency and ATP production are predominantly driven by the high sensitivity of substrate oxidation and proton leak subsystems to this metal.

Short-term acute hypercapnia affects cellular responses to trace metals in the hard clams Mercenaria mercenaria

Estuarine and coastal habitats experience large fluctuations of environmental factors such as temperature, salinity, partial pressure of CO2 ( [Formula: see text] ) and pH; they also serve as the natural sinks for trace metals. Benthic filter-feeding organisms such as bivalves are exposed to the elevated concentrations of metals in estuarine water and sediments that can strongly affect their physiology. The effects of metals on estuarine organisms may be exacerbated by other environmental factors. Thus, a decrease in pH caused by high [Formula: see text] (hypercapnia) can modulate the effects of trace metals by affecting metal bioavailability, accumulation or binding. To better understand the cellular mechanisms of interactions between [Formula: see text] and trace metals in marine bivalves, we exposed isolated mantle cells of the hard clams (Mercenaria mercenaria) to different levels of [Formula: see text] (0.05, 1.52 and 3.01 kPa) and two major trace metal pollutants - cadmium (Cd) and copper (Cu). Elevated [Formula: see text] resulted in a decrease in intracellular pH (pHi) of the isolated mantle cells from 7.8 to 7.4. Elevated [Formula: see text] significantly but differently affected the trace metal accumulation by the cells. Cd uptake was suppressed at elevated [Formula: see text] levels while Cu accumulation has greatly accelerated under hypercapnic conditions. Interestingly, at higher extracellular Cd levels, labile intracellular Cd(2+) concentration remained the same, while intracellular levels of free Zn(2+) increased suggesting that Cd(2+) substitutes bound Zn(2+) in these cells. In contrast, Cu exposure did not affect intracellular Zn(2+) but led to a profound increase in the intracellular levels of labile Cu(2+) and Fe(2+). An increase in the extracellular concentrations of Cd and Cu led to the elevated production of reactive oxygen species under the normocapnic conditions (0.05 kPa [Formula: see text] ); surprisingly, this effect was mitigated in hypercapnia (1.52 and 3.01 kPa). Overall, our data reveal complex and metal-specific interactions between the cellular effects of trace metals and [Formula: see text] in clams and indicate that variations in environmental [Formula: see text] may modulate the biological effects of trace metals in marine organisms.

anti-Tricyclo­[4.2.1.12,5]deca-3,7-diene-9-endo,10-endo-diol

The title compound, C10H12O2, was synthesized as a candidate for further functionalization. The asymmetric unit comprises two independent molecules, both of which are situated on a center of symmetry. Both molecules are involved in a network of hydrogen bonding, with each alcohol group participating in one hydrogen bond as a donor and in a second hydrogen bond as an acceptor.

Preparation, structures and preliminary host–guest studies of fluorinated syn-bis-quinoxaline molecular tweezers

Summary A series of polycyclic frameworks with fluorinated syn-facial quinoxaline sidewalls has been prepared as potential molecular tweezers for electron-rich guest compounds. Our synthetic route to the cyclooctadiene-derived scaffolds 16a–d takes advantage of the facile isolation of a novel spirocyclic precursor 9b with the crucial syn-orientation of its two alkene moieties. The crystal structure of 16c displays two features typical of a molecular tweezer: inclusion of a solvent molecule in the molecular cleft and self-association of the self-complementary scaffolds. Furthermore, host–guest NMR studies of compound 16c in solution show chemical exchange between the unbound and bound electron-rich guest, N,N,N′,N′-tetramethyl-p-phenylenediamine.

anti-Tricyclo­[4.2.1.12,5]deca-3,7-diene-9,10-dione

The title compound, C10H8O2, is a precursor to an unusual bis-homoaromatic dication and to heterodiamantanes and other oxa-cage compounds. Two independent molecules, each of which is situated on a center of symmetry, comprise the unit cell. Both molecules are in nearly identical chair conformations.

syn-Dispiro­[1,3-dioxolane-2,17′-penta­cyclo­[12.2.1.16,9.02,13.05,10]octa­decane-18′,2′′-[1,3]dioxolane]-7′,15′-diene

The title compound, C22H28O4, is composed of a central octadecane ring and two spiro[bicyclo[2.2.1]hept[2]ene-7,2′-[1,3]dioxolane] units. This polycycle has pseudo twofold symmetry and the central cyclooctane ring has a distorted boat configuration.

anti-1′,6′,7′,8′,9′,14′,15′,16′-Octa­chloro­dispiro­[1,3-dioxolane-2,17′-penta­cyclo­[12.2.1.16,9.02,13.05,10]octa­decane-18′,2′′-1,3-dioxolane]-7′,15′-diene

The title compound, C22H20Cl8O4, was prepared as part of the synthesis of precursors for the preparation of fluorinated molecular tweezers. The molecule sits on an inversion center, thus requiring that the cyclooctane ring adopt a chair conformation.

cis-9,10-Bis(bromo­meth­yl)-1,4,5,8-tetra­oxadeca­lin

The title compound, C8H12Br2O4, is a bicyclic ketal in which the two six-membered rings are cis to one another and assume a double-chair conformation. A crystallographic twofold axis bisects the molecule.