Structures and functions of mitochondrial ABC transporters

A small number of physiologically important ATP-binding cassette (ABC) transporters are found in mitochondria. Most are half transporters of the B group forming homodimers and their topology suggests they function as exporters. The results of mutant studies point towards involvement in iron cofactor biosynthesis. In particular, ABC subfamily B member 7 (ABCB7) and its homologues in yeast and plants are required for iron-sulfur (Fe-S) cluster biosynthesis outside of the mitochondria, whereas ABCB10 is involved in haem biosynthesis. They also play a role in preventing oxidative stress. Mutations in ABCB6 and ABCB7 have been linked to human disease. Recent crystal structures of yeast Atm1 and human ABCB10 have been key to identifying substrate-binding sites and transport mechanisms. Combined with in vitro and in vivo studies, progress is being made to find the physiological substrates of the different mitochondrial ABC transporters

Human Iron−Sulfur Cluster Assembly, Cellular Iron Homeostasis, and Disease†

ABSTRACT: Iron-sulfur (Fe-S) proteins contain prosthetic groups consisting of two or more iron atoms bridged by sulfur ligands, which facilitate multiple functions, including redox activity, enzymatic function, and maintenance of structural integrity. More than 20 proteins are involved in the biosynthesis of iron-sulfur clusters in eukaryotes. Defective Fe-S cluster synthesis not only affects activities of many iron-sulfur enzymes, such as aconitase and succinate dehydrogenase, but also alters the regulation of cellular iron homeostasis, causing both mitochondrial iron overload and cytosolic iron deficiency. In this work, we review human Fe-S cluster biogenesis and human diseases that are caused by defective Fe-S cluster biogenesis. Fe-S cluster biogenesis takes place essentially in every tissue of humans, and products of human disease genes, including frataxin, GLRX5, ISCU, and ABCB7, have important roles in the process. However, the human diseases, Friedreich ataxia, glutaredoxin 5-deficient sideroblastic anemia, ISCU myopathy, and ABCB7 sideroblastic anemia/ataxia syndrome, affect specific tissues, while sparing others. Here we discuss the phenotypes caused by mutations in these different disease genes, and we compare the underlying pathophysiology and discuss the possible explanations for tissue-specific pathology in these diseases caused by defective Fe-S cluster biogenesis. HUMAN CELLULAR IRON HOMEOSTASI

Multisegmented tangential breast fields: A rational way to treat breast cancer

Purpose: Using three-dimensional conformal radiation therapy (3D-CRT) and multisegmented conformal radiation therapy (MS-CRT) for breast cancer treatment, the dose coverage of the planning target volume (PTV) and the radiation burden on the organs at risk (OARs) were evaluated. Material and Methods: 3D-CRT and MS-CRT were planned for 436 unilateral breasts (217 left). All patients were treated with MS-CRT between 2005 and 2007. For PTV delineation and beam orientation, supportive structures were applied. The mean PTV was 1,130 cm 3 (in ten patients > 2,200 cm3). Three-dimensional planning with weight-optimized medial and lateral open fields at a total dose of 50.4/1.8 Gy was followed by multisegmented planning with a reasonably high-dose-level dose cloud to define the medial subfield, and renewed optimization. This was repeated for the lateral subfield with a final optimization. For PTV coverage evaluation, the ICRU 50 was considered: the PTV portions receiving 95-107%, 107% of the prescribed dose (PTVD95- 107%, PTVD107%), and the PTV maximal dose (PTVDmax). To compare the OAR radiation burdens, the mean doses to the ipsi-/contralateral lung, contralateral breast, and whole heart were documented. Results: The multisegmented plans furnished significantly (p D107% 5.9% vs. 0.3% and PTVDmax 56.6 vs. 54.3 Gy). The mean OAR doses remained almost unchanged: ipsilateral lung 10.5 versus 10.4 Gy, contralateral lung 0.4 versus 0.4 Gy, contralateral breast 0.8 versus 0.8 Gy, and whole heart (for left-sided cancers) 4.8 versus 4.8 Gy. The subfields required a mean of 9.8 MU (monitor units), i.e., a mean total 7.6 MU increment. The planning took 10-20 min, and the delivery 5-10 min. Conclusion: MS-CRT is a good alternative to breast intensity-modulated radiation therapy (IMRT) and seems adequate for right-sided cancers, whereas left-sided cancers necessitate a longer follow-up of heart-related side effects before a final assessment. © 2008 Urban & Vogel

Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex.

The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery

The Evolution and Devolution of Speed Limit Law and the Effect on Fatality Rates

The three most recent decades provide an outstanding opportunity to study the changing federalist landscape concerning the regulation of speed on the nation's highways. Speed limits were the province of the states until the 1970s when, in an effort to save energy, the central government nationalized the maximum speed at 55 miles per hour. The national standard remained until the 1980s, when a partial devolution transferred some power to set speed limits back to the individual states. At that time, states could increase the maximum speed to 65 miles per hour on (at fewest) four-lane, controlled access highways in low population density areas. Some states elected to loosen the limits within their borders, while others did not, citing concerns of highway safety as paramount. The 1990s saw the complete devolution of speed limit control to the states, when Congress returned to the states unlimited control. States reacted differently in both of the two latter phases, providing a fruitful landscape for comparative analysis of the effects of the devolution of speed limit control. Copyright 2005 by The Policy Studies Organization.