TLR9-mediated invasion may represent a novel mechanism through which infections promote prostate cancer.

Obesity-related pathologies, such as nonalcoholic fatty liver disease, are linked to mitochondrial dysfunction and nitric oxide (NO) deficiency. Herein, we tested the hypothesis that a high-fat diet (HFD) modifies the liver mitochondrial proteome and alters proteins involved in NO metabolism, namely arginase 1 and endothelial NO synthase. Male C57BL/6 mice were fed a control or HFD and liver mitochondria were isolated for proteomics and reactive oxygen species measurements. Steatosis and hepatocyte ballooning were present in livers of HFD mice, with no pathology observed in the controls. HFD mice had increased serum glucose and decreased adiponectin. Mitochondrial reactive oxygen species was increased after 8 weeks in the HFD mice, but decreased at 16 weeks compared with the control, which was accompanied by increased uncoupling protein 2. Using proteomics, 22 proteins were altered as a consequence of the HFD. This cohort consists of oxidative phosphorylation, lipid metabolism, sulfur amino acid metabolism, and chaperone proteins. We observed a HFD-dependent increase in arginase 1 and decrease in activated endothelial NO synthase. Serum and liver nitrate + nitrite were decreased by HFD. In summary, these data demonstrate that a HFD causes steatosis, alters NO metabolism, and modifies the liver mitochondrial proteome; thus, NO may play an important role in the processes responsible for nonalcoholic fatty liver disease.

MIC-1 up-regulates TLR9 expression in various cells. MIC-1 stimulates both osteoblast and osteoclast differentiation in vitro, independently of TLR9. MIC-1 over-expressing prostate cancer cells that grow in bone induce osteoclast formation and cachexia.

King AL, Swain TM, Dickinson DA, Lesort MJ, Bailey SM. Chronic ethanol consumption enhances sensitivity to Ca 2ϩ -mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver.

Chronic ethanol consumption increases sensitivity of the mitochondrial permeability transition (MPT) pore induction in liver. Ca 2ϩ promotes MPT pore opening, and genetic ablation of cyclophilin D (CypD) increases the Ca 2ϩ threshold for the MPT. We used wild-type (WT) and CypD-null (CypD Ϫ/Ϫ ) mice fed a control or an ethanol-containing diet to investigate the role of the MPT in ethanol-mediated liver injury. Ca 2ϩ -mediated induction of the MPT and mitochondrial respiration were measured in isolated liver mitochondria. Steatosis was present in WT and CypD Ϫ/Ϫ mice fed ethanol and accompanied by increased terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive nuclei. Autophagy was increased in ethanol-fed WT mice compared with ethanol-fed CypD Ϫ/Ϫ mice, as reflected by an increase in the ratio of microtubule protein 1 light chain 3B II to microtubule protein 1 light chain 3B I. Higher levels of p62 were measured in CypD Ϫ/Ϫ than WT mice. Ethanol decreased mitochondrial respiratory control ratios and select complex activities in WT and CypD Ϫ/Ϫ mice. Ethanol also increased CypD protein in liver of WT mice. Mitochondria from control-and ethanol-fed WT mice were more sensitive to Ca 2ϩ -mediated MPT pore induction than mitochondria from their CypD Ϫ/Ϫ counterparts. Mitochondria from ethanol-fed CypD Ϫ/Ϫ mice were also more sensitive to Ca 2ϩ -induced swelling than mitochondria from control-fed CypD Ϫ/Ϫ mice but were less sensitive than mitochondria from ethanol-fed WT mice. In summary, CypD deficiency was associated with impaired autophagy and did not prevent ethanol-mediated steatosis. Furthermore, increased MPT sensitivity was observed in mitochondria from ethanol-fed WT and CypD Ϫ/Ϫ mice. We conclude that chronic ethanol consumption likely lowers the threshold for CypD-regulated and -independent characteristics of the ethanol-mediated MPT pore in liver mitochondria.liver; mitochondria; alcohol; cyclophilin D; permeability transition pore CHRONIC ETHANOL CONSUMPTION causes liver injury, with some of the earliest pathological changes observed in the mitochondrion (31, 59). These ethanol-mediated alterations include changes in mitochondrial morphology (e.g., enlarged, misshapen mitochondria with fewer cristae) (26) and increased production of reactive oxygen species (ROS) from the organelle (6). Increased mitochondrial ROS production is recognized as a critical component in the cellular stress response induced by ethanol (18,60). Chronic ethanol consumption also damages mitochondrial DNA and ribosomes, inhibits mitochondrial protein synthesis, decreases oxidative phosphorylation, and depresses ATP synthesis (59). Studies by Pastorino and colleagues (66,67) show that chronic ethanol consumption stimulates formation of the mitochondrial permeability transition (MPT) pore. However, the mechanisms responsible for this effect remain poorly defined.MPT pore induction is characterized as increased permeability of the inner mitochondrial membrane to water and solutes (39,41). This causes depolarizatio...