1,721,077 research outputs found
Towards a therapy for mitochondrial disease: an update
Full text linkPreclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different
approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field
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Breathe: Your Mitochondria Will Do the Rest… If They Are Healthy!
Full text linkDysfunctions of the mitochondrial electron transport chain cause severe, currently untreatable, diseases in humans. A new study by Jain et al. (2019) reports increased oxygen levels in the brain of complex-I-deficient mice. Reducing the O2 levels by hypoxia, carbon monoxide, or anemia, improved the clinical phenotype and prolonged the lifespan of the mouse model
MtDNA-maintenance defects: syndromes and genes
Full text linkA large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions.
Communicated by: Shamima Rahman
Presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Rome, Italy, September 6–9, 201
Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models
Full text linkThe fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders
Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity
Full text linkMice lacking Surf1, a complex IV assembly protein, have 50-70% reduction in cytochrome c oxidase activity in all tissues yet a paradoxical increase in lifespan. Here we report that Surf1-/- mice have lower body (15%) and fat (20%) mass, in association with reduced lipid storage, smaller adipocytes, and elevated indicators of fatty acid oxidation in white adipose tissue (WAT) compared with control mice. The respiratory quotient in the Surf1-/- mice was significantly lower than in the control animals (0.83- 0.93 vs. 0.90-0.98), consistent with enhanced fat utilization in Surf1-/- mice. Elevated fat utilization was associated with increased insulin sensitivity measured as insulinstimulated glucose uptake, as well as an increase in insulin receptor levels (2-fold) and glucose transporter type 4 (GLUT4; 1.3-fold) levels in WAT in the Surf1-/- mice. The expression of peroxisome proliferator- activated receptor β-coactivator 1 (PGC-1α) mRNA and protein was up-regulated by 2.5- and 1.9- fold, respectively, in WAT from Surf1-/- mice, and the expression of PGC-1α target genes and markers of mitochondrial biogenesis was elevated. Together, these findings point to a novel and unexpected link between reduced mitochondrial complex IV activity, enhanced insulin sensitivity, and increased mitochondrial biogenesis that may contribute to the increased longevity in the Surf1-/- mice.-Deepa, S. S., Pulliam, D., Hill, S., Shi, Y., Walsh, M. E., Salmon, A., Sloane, L., Zhang, N., Zeviani, M., Viscomi, C., Musi, N., Van Remmen, H. Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity. FASEB J. 27, 1371-1380 (2013). www.fasebj.org
Physical and functional cross talk between endo-sarcoplasmic reticulum and mitochondria in skeletal muscle
No full textSignificance: The physiological relevance of contacts between the sarcoplasmic reticulum (SR), a specialized domain of the endoplasmic reticulum (ER) in skeletal muscle, and mitochondria is still not clear. Recent Advances: An extensive close proximity of these two organelles is a late developmental event, which suggests that it does not have an essential function. Critical Issues: The intimate association of SR/mitochondria develops during murine postnatal differentiation and the recovery of denervated atrophic muscle, which suggests that this is a highly regulated process with a specific function. Analyses of mouse models for muscle diseases suggest that impaired ER/SR-mitochondrial contacts may be due to ER stress and lead to defective bioenergetics and insulin signaling. Future Directions: Future studies are necessary to identify the molecular determinants weakening insulin signaling upon impairment of ER/mitochondrial contacts in skeletal muscles as well as to analyze the distance between SR/ER and mitochondria in muscle diseases associated with ER stress
Human common fragile sites FRA2H and FRA7B.
No full textThe chromosomes of all analysed individuals show gaps or breaks in specific regions, the common fragile sites (CFS) (n = 100), when the cells are exposed to replication stress or to some DNA-binding compounds. So, they are “normal” features of human genome, but the frequency of their expression is different in different individuals. CFSs cause genetic instability and are frequently involved in mutations in cancer cells. The causes of their fragility are still under investigation. The analysis of the twenty CFSs until now molecularly characterized revealed same shared features: the AT bases richness, the high DNA flexibility and the DNA late replication.
In this work we determined the DNA sequence of the CFS FRA2H (2q32.1-q32.2) and of the telomeric fragile site FRA7B (7p22.3-p21.3) using BAC clones and fluorescent in situ hybridization (FISH). The expression of both CFSs is induced by aphidicolin. FRA7B is also inducible by DAPI (4’,6-diamidino-2-phenylindole). We analysed the molecular composition of these two sequences and searched for the presence of DNA helix high flexibility regions.
The chromosome bands 2q32.1 and 7p22 are recurrent breakpoints in chromosome abnormalities in different types of neoplasms
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