Mitochondrial genome and diverse inheritance patterns in Pleurotus pulmonarius.

Pleurotus pulmonarius, a member of the Pleurotaceae family in Basidiomycota, is an edible, economically important mushroom in most Asian countries. In this study, the complete mitochondrial genomes (mtDNA) of three P. pulmonarius strains - two monokaryotic commercial (J1-13 and ZA3) and one wild (X1-15) - were sequenced and analyzed. In ZA3 and X1-15, the mtDNA molecule was found to be a single circle of 68,305 bp and 73,435 bp, respectively. Both strains contain 14 core protein-coding genes and two ribosomal RNA (rRNA) subunit genes. The ZA3 strain has 22 transfer RNA (tRNA) genes and nine introns: eight in cytochrome c oxidase subunit 1 (coxl), and one in the rRNA large subunit (rnl). Monokaryotic J1-13 and ZA3 mtDNAs were found to be similar in their structure. However, the wild strain X1-15 contains 25 tRNA genes and only seven introns in coxl. Open reading frames (ORFs) of ZA3/J1-13 and X1-15 encode LAGLIDADG, ribosomal protein S3, and DNA polymerase II. In addition, mtDNA inheritance in J1-13, ZA3, and X1-15 was also studied. Results showed that the mtDNA inheritance pattern was uniparental and closely related to dikaryotic hyphal location with respect to the parent. Results also show that mtDNA inheritance is influenced by both the parental nuclear genome and mitogenome in the zone of contact between two compatible parents. In summary, this analysis provides valuable information and a basis for further studies to improve our understanding of the inheritance of fungal mtDNA.

An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model.

Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases (Nox) are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the Nox4 isoform is up-regulated in the lungs of patients with IPF and in a rodent model of bleomycin-induced pulmonary fibrosis and vascular remodeling. Nox4 is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule Nox4/Nox1 inhibitor, we demonstrate that targeting Nox4 results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1α1, collagen 3α1, and fibronectin and in principle pathway components associated with pulmonary fibrosis and hypoxia-mediated vascular remodeling: transforming growth factor (TGF)-ß1, plasminogen activator inhibitor-1, hypoxia-inducible factor, and Nox4. TGF-ß1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of Nox4 activity using a small molecule antagonist attenuates TGF-ß1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting Nox4 may provide a therapeutic approach for attenuating pulmonary fibrosis.