Mitochondrial DNA (mtDNA) maintenance disorders are caused by mutations in ubiquitously expressed nuclear genes and lead to syndromes with variable disease severity and tissue-specific phenotypes. Loss of function mutations in the gene encoding the mitochondrial genome and maintenance exonuclease 1 (MGME1) result in deletions and depletion of mtDNA leading to adult-onset multisystem mitochondrial disease in humans. To better understand the in vivo function of MGME1 and the associated disease pathophysiology, we characterized a Mgme1 mouse knockout model by extensive phenotyping of ageing knockout animals. We show that loss of MGME1 leads to de novo formation of linear deleted mtDNA fragments that are constantly made and degraded. These findings contradict previous proposal that MGME1 is essential for degradation of linear mtDNA fragments and instead support a model where MGME1 has a critical role in completion of mtDNA replication. We report that Mgme1 knockout mice develop a dramatic phenotype as they age and display progressive weight loss, cataract and retinopathy. Surprisingly, aged animals also develop kidney inflammation, glomerular changes and severe chronic progressive nephropathy, consistent with nephrotic syndrome. These findings link the faulty mtDNA synthesis to severe inflammatory disease and thus show that defective mtDNA replication can trigger an immune response that causes age-associated progressive pathology in the kidney. 相似文献
In this work, a method for improved protein identification of low-abundance proteins using unstained gels, in combination with robotics and matrix-assisted laser desorption/ionization tandem mass spectrometry, has been developed and evaluated. Omitting the silver-staining process resulted in increased protein identification scores, an increase in the number of peptides observed in the MALDI mass spectrum, and improved quality of the tandem mass spectrometry data. 相似文献
Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T?>?G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T?>?G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44-related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement.
The effect of a strong electric field generated by molecular dipoles on the ground state electronic structure and the Q and B states as well as the lowest charge transfer (CT) excited state of porphine–2,5-dimethyl-1,4-benzoquinone (PQ) complex has been investigated theoretically. Density functional theory DFT and time-dependent DFT (TDDFT) with the BH&HLYP hybrid functional have been applied in these calculations. The molecular dipole effect was generated by imposing one or two helical homopeptides consisting of eight α-aminoisobutyric acid residues (Aib8) close to the PQ complex. The molecular dipoles in a close proximity to the PQ complex expose it to an electric field of the order of magnitude of 109 V/m. The presence of the ambient molecular dipoles affects mainly the energy of the lowest CT state and barely the energies of the Q and B states. The molecular dipoles affect the energies of the excited states in a similar way as an external electrostatic field. Hence, the electric field induced by the molecular dipoles of the helical peptides could be used analogously to the external electrostatic field to control electron transfer (ET) in the PQ complex. 相似文献
Macrophage migration into injured or infected tissue is a key aspect in the pathophysiology of many diseases where inflammation is a driving factor. Membrane‐type‐1 matrix metalloproteinase (MT1‐MMP) cleaves extracellular matrix components to facilitate invasion. Here we show that, unlike the constitutive MT1‐MMP surface recycling seen in cancer cells, unactivated macrophages express low levels of MT1‐MMP. Upon lipopolysaccharide (LPS) activation, MT1‐MMP synthesis dramatically increases 10‐fold at the surface by 15 hours. MT1‐MMP is trafficked from the Golgi complex to the surface via late endosomes/lysosomes in a pathway regulated by the late endosome/lysosome R‐SNAREs VAMP7 and VAMP8. These form two separate complexes with the surface Q‐SNARE complex Stx4/SNAP23 to regulate MT1‐MMP delivery to the plasma membrane. Loss of either one of these SNAREs leads to a reduction in surface MT1‐MMP, gelatinase activity and reduced invasion. Thus, inhibiting MT1‐MMP transport through this pathway could reduce macrophage migration and the resulting inflammation. 相似文献
The multidisciplinarity of integrative taxonomy is particularly useful for clarifying the systematics of speciose groups that are poorly differentiated morphologically, and this approach can also illuminate their evolutionary history and biogeography. Here, we utilize it to examine the systematics and taxonomy of a newly recognized amphipod species, Gammarus hamaticornis n. sp., which belongs to a highly diverse genus of endemic freshwater crustaceans that show very limited morphological differentiation. Since this species is endemic to northern Dobrogea, a region at the northwestern Black Sea coast devoid of permafrost during the Last Glacial Maximum, we hypothesized that it survived in situ during the Quaternary climatic oscillations. We first examined the phylogenetic position of Gammarus hamaticornis n. sp. within the genus and then compared its morphology, phylogeography, distribution, and climatic niche with that of its sister species. Results indicate that G. hamaticornis n. sp. is most closely related to its widely distributed northern neighbor, G. kischineffensis, and a remarkable agreement was observed among morphological, multilocus coalescent and climatic analyses which supported the distinctiveness of both taxa. These apparently diverged during the Pliocene from a common ancestor that likely colonized freshwaters from the adjacent brackish basins of the shrinking Paratethys. The results indicate that G. hamaticornis n. sp. has persisted throughout the Pleistocene in northern Dobrogea, a hitherto hypothesized refugium confirmed for the first time with molecular genetic data. Due to its narrow geographical range, rarity in the local communities and highly fluctuating nature of the streams it inhabits, this species should be in the focus of future conservation priorities. 相似文献
Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a beta-structure conformation and hence to aggregate. The "pro-aggregation" mutant DeltaK280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant DeltaK280/PP cannot aggregate because of two beta-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the anti-aggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses. 相似文献
Photosynthesis Research - Cyanobacteria, as well as green algae and higher plants, have highly conserved photosynthetic machinery. Cyanothece sp. ATCC 51142 is a unicellular, aerobic, diazotrophic... 相似文献