Probing the Outer Mitochondrial Membrane in Cardiac Mitochondria with Nanoparticles

AbstractThe outer mitochondrial membrane (OMM) is the last barrier between the mitochondrion and the cytoplasm. Breaches of OMM integrity result in the release of cytochrome c oxidase, triggering apoptosis. In this study, we used calibrated gold nanoparticles to probe the OMM in rat permeabilized ventricular cells and in isolated cardiac mitochondria under quasi-physiological ionic conditions and during permeability transition. Our experiments showed that under control conditions, the OMM is not permeable to 6-nm particles. However, 3-nm particles could enter the mitochondrial intermembrane space in mitochondria of permeabilized cells and isolated cardiac mitochondria. Known inhibitors of the voltage-dependent anion channel (VDAC), König polyanion, and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid inhibited this entrance. Thus, 3-nm particles must have entered the mitochondrial intermembrane space through the VDAC. The permeation of the isolated cardiac mitochondria OMM for 3-nm particles was ∼20 times that in permeabilized cells, suggesting low availability of VDAC pores within the cell. Experiments with expressed green fluorescent protein showed the existence of intracellular barriers restricting the VDAC pore availability in vivo. Thus, our data showed that 1), the physical diameter of VDAC pores in cardiac mitochondria is ≥3nm but ≤6nm, and 2), permeability transition-related mitochondrial swelling results in breaching and disruption of the OMM

Perturbation theory for domain walls in the parametric Ginzburg-Landau equation

We demonstrate that in the parametrically driven Ginzburg-Landau equation arbitrarily small nongradient corrections lead to qualitative differences in the dynamical properties of domain walls in the vicinity of the transition from rest to motion. These differences originate from singular rotation of the eigenvector governing the transition. We present analytical results on the stability of Ising walls, deriving explicit expressions for the critical eigenvalue responsible for the transition from rest to motion. We then develop a weakly nonlinear theory to characterize the singular character of the transition and analyze the dynamical effects of spatial inhomogeneities

FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death

AbstractArrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca2+ release and cardiac contractility. FKBP12.6−/− mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that “leaky” RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT

Single-particle shell strengths near the doubly magic nucleus 56Ni and the 56Ni(p,γ)57Cu reaction rate in explosive astrophysical burning

Angle-integrated cross-section measurements of the 56Ni(d,n) and (d,p) stripping reactions have been performed to determine the single-particle strengths of low-lying excited states in the mirror nuclei pair 57Cu−57Ni situated adjacent to the doubly magic nucleus 56Ni. The reactions were studied in inverse kinematics utilizing a beam of radioactive 56Ni ions in conjunction with the GRETINA γ-array. Spectroscopic factors are compared with new shell-model calculations using a full pf model space with the GPFX1A Hamiltonian for the isospin-conserving strong interaction plus Coulomb and charge-dependent Hamiltonians. These results were used to set new constraints on the 56Ni(p,γ)57Cu reaction rate for explosive burning conditions in x-ray bursts, where 56Ni represents a key waiting point in the astrophysical rp-process.peerReviewe