This review on recent research advances of the lipid peroxidation product 4-hydroxy-nonenal (HNE) has four major topics: I. the formation of HNE in various organs and tissues, II. the diverse biochemical reactions with Michael adduct formation as the most prominent one, III. the endogenous targets of HNE, primarily peptides and proteins (here the mechanisms of covalent adduct formation are described and the (patho-) physiological consequences discussed), and IV. the metabolism of HNE leading to a great number of degradation products, some of which are excreted in urine and may serve as non-invasive biomarkers of oxidative stress.

Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress-i.e., enhanced formation of reactive oxygen species (ROS)-however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress.Keywords: iron; oxidative stress; metabolism Systemic and Cellular Iron TransfersFerric iron or iron contained in heme is absorbed by intestinal enterocytes via heme carrier proteins (HCP1) [1], the divalent metal transporter DMT1 (SLC11A2) [2,3] or the integrin-mobilferrin pathway [4,5] (a review on intestinal iron absorption is given in [6,7]). The absorbed iron is then released from the enterocytes to the bloodstream as transferrin-bound iron (TBI) via ferroportin (see below). Under physiological conditions, the bulk of iron enters the cell bound as TBI via transferrin-receptor (TfR) mediated endocytosis followed by endosomal iron liberation. However, resorption of non-transferrin OPEN ACCESSBiomolecules 2015, 5 809 bound iron (NTBI) from the bloodstream may also occur either via DMT-1, the zinc transporter Zip14 (SLC39A14) [8,9] or specific citrate binding sites [10][11][12]. Notably, the serum content of labile NTBI is very low under normal conditions but may rise substantially in diseased states, such as thalassemia, where the high NTBI level-essentially caused by repeated blood transfusion-is considered to cause disease-related oxidative stress [13][14][15][16][17][18]. Similarly, serum ferritin which may serve as iron carrier too [19,20] and is also increased under certain pathological conditions, such as inflammation and cancer [21], can also be endocytosed [22][23][24][25] [34]. Finally, heme-bound iron will enter the cells via HCP1 [1] and tissue macrophages will also "ingest iron" upon phagocytosis of aged cells such as erythrocytes or via the haptoglobin/CD 163 or hemopexin/CD91 mediated uptake of hemoglobin or heme [35] and deliver the recycled iron back to the bloodstream, which is indispensable for the maintenance of systemic iron homeostasis [36].In contrast to several ways of cellular iron uptake, only two mechanisms of cellular iron release are known. Usually, iron release from a cell occurs via ferroportin (Fpn) [37][38][39][40][41] a membrane bound iron exporter, which is controlled by hepatocyte derived hepcidin [42,43], the hepcidin activity itself being regulated by the serine protease matriptase-2 [44,45]. The ferroportin-rel...

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In recent years it turned out that there is not only extensive communication between the nucleus and mitochondria but also between mitochondria and lipid droplets (LDs) as well. We were able to demonstrate that a number of proteins shuttle between LDs and mitochondria and it depends on the metabolic state of the cell on which organelle these proteins are predominantly localized. Responsible for the localization of the particular proteins is a protein domain consisting of two α-helices, which we termed V-domain according to the predicted structure. So far we have detected this domain in the following proteins: mammalian BAX, BCL-XL, TCTP and yeast Mmi1p and Erg6p. According to our experiments there are two functions of this domain: (1) shuttling of proteins to mitochondria in times of stress and apoptosis; (2) clearing the outer mitochondrial membrane from pro- as well as anti-apoptotic proteins by moving them to LDs after the stress ceases. In this way the LDs are used by the cell to modulate stress response.

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