Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis.

BACKGROUND AND PURPOSE: Cardiolipin plays an important role in mitochondrial respiration and cardiolipin peroxidation is associated with age-related diseases. Hydrophobic interactions between cytochrome c and cardiolipin converts cytochrome c from an electron carrier to a peroxidase. In addition to cardiolipin peroxidation, this impedes electron flux and inhibits mitochondrial ATP synthesis. SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2 ) selectively binds to cardiolipin and inhibits cytochrome c peroxidase activity. Here, we examined whether SS-31 also protected the electron carrier function of cytochrome c. EXPERIMENTAL APPROACH: Interactions of SS-31 with cardiolipin were studied using liposomes and bicelles containing phosphatidylcholine alone or with cardiolipin. Structural interactions were assessed by fluorescence spectroscopy, turbidity and nuclear magnetic resonance. Effects of cardiolipin on electron transfer kinetics of cytochrome c were determined by cytochrome c reduction in vitro and oxygen consumption using mitoplasts, frozen and fresh mitochondria. KEY RESULTS: SS-31 interacted only with liposomes and bicelles containing cardiolipin in about 1:1 ratio. NMR studies demonstrated that the aromatic residues of SS-31 penetrated deep into cardiolipin-containing bilayers. SS-31 restored cytochrome c reduction and mitochondrial oxygen consumption in the presence of added cardiolipin. In fresh mitochondria, SS-31 increased state 3 respiration and efficiency of ATP synthesis. CONCLUSIONS AND IMPLICATIONS: SS-31 selectively targeted cardiolipin and modulated its interaction with cytochrome c. SS-31 inhibited the cytochrome c/cardiolipin complex peroxidase activity while protecting its ability to serve as an electron carrier, thus optimizing mitochondrial electron transport and ATP synthesis. This novel class of cardiolipin therapeutics has the potential to restore mitochondrial bioenergetics for treatment of numerous age-related diseases.

Male pelvic anatomy reconstructed from the visible human data set.

PURPOSE: To improve understanding of the male pelvic anatomy pertinent to urological surgery we performed computer generated, 3-dimensional reconstruction of the male pelvis from the Visible Human data set. MATERIALS AND METHODS: A total of 18 discrete anatomical structures, including the prostate, bladder, urethra, rectum and pelvic musculature, was segmented from the Visible Human cross-sectional data obtained from the National Library of Medicine. Using high speed computing and rendering software, 3-dimensional models of each structure were generated and assembled into composite figures. RESULTS: These reconstructions offer a revised view of pelvic anatomy as it has been traditionally depicted. The lateral surfaces of the levator ani muscle are oriented vertically in the pelvis and directly applied to the entire lateral surface of the prostate. The bladder rests primarily anterior to the prostate rather than directly above it, as has been commonly depicted. In the cross-sectional data and reconstructions the trigone and anterior fibromuscular stroma of the prostate appear as a single unit in continuity, which may have functional implications for understanding the mechanisms of continence at the bladder neck. The striated urethral sphincter appears circular with abundant tissue posteriorly. This sphincteric muscle has greater length anteriorly than posteriorly. CONCLUSIONS: These 3-dimensional reconstructions provide unique insights into male pelvic anatomy. They are a useful teaching tool for investigation and virtual reality modeling of the male pelvis.