Heart failure is a major public health problem, and abnormal iron metabolism is common in patients with heart failure. Although iron is necessary for metabolic homeostasis, it induces a programmed necrosis. Iron release from ferritin storage is through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear. Deletion of Ncoa4 in mouse hearts reduced left ventricular chamber size and improved cardiac function along with the attenuation of the upregulation of ferritinophagy-mediated ferritin degradation 4 weeks after pressure overload. Free ferrous iron overload and increased lipid peroxidation were suppressed in NCOA4-deficient hearts. A potent inhibitor of lipid peroxidation, ferrostatin-1, significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice. Thus, the activation of ferritinophagy results in the development of heart failure, whereas inhibition of this process protects the heart against hemodynamic stress.

The Z-disk is a complex structure comprising some 40 proteins that are involved in the transmission of force developed during muscle contraction and in important signalling pathways that govern muscle homeostasis. In the Z-disk the ends of antiparallel thin filaments from adjacent sarcomeres are crosslinked by α-actinin. The structure of the Z-disk lattice varies greatly throughout the animal kingdom. In vertebrates the thin filaments form a tetragonal lattice, whereas invertebrate flight muscle has a hexagonal lattice. The width of the Z-disk varies considerably and correlates with the number of α-actinin bridges. A detailed description at a high resolution of the Z-disk lattice is needed in order to better understand muscle function and disease. The molecular architecture of the Z-disk lattice in honeybee (Apis mellifera) is known from plastic embedded thin sections to a resolution of 7 nm, which is not sufficient to dock component protein crystal structures. It has been shown that sectioning is a damaging process that leads to the loss of finer details present in biological specimens. However, the Apis Z-disk is a thin structure (120 nm) suitable for cryo EM. We have isolated intact honeybee Z-disks from indirect flight muscle, thus obviating the need of plastic sectioning. We have employed cryo electron tomography and image processing to investigate the arrangement of proteins within the hexagonal lattice of the Apis Z-disk. The resolution obtained, ~6 nm, was probably limited by damage caused by the harshness of the conditions used to extract the myofibrils and isolate the Z-disks.Electronic supplementary materialThe online version of this article (doi:10.1007/s10974-017-9477-5) contains supplementary material, which is available to authorized users.

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