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Mitochondrial disorder

Alan Pestronk, Richard Keeling, Rati Choksi
OBJECTIVE: We studied mitochondrial impairment as a factor in the pathologic equivalent of sarcopenia, muscle fiber atrophy associated with increased age. METHODS: Mitochondrial oxidative enzyme activities and coenzyme Q10 levels were measured in frozen human proximal limb muscles with combined age and atrophy, age alone, atrophy alone, denervation, immune myopathies, and mitochondrial disorders with ophthalmoplegia. RESULTS: Sarcopenia (age and atrophy) had reduced mean activities of mitochondrial Complexes I, II, and II+III, with severe reduction of Complex I activity in 54% of patients...
October 19, 2016: Muscle & Nerve
Kazumasa Fuwa, Mitsuru Kubota, Masami Kanno, Hiroshi Miyabayashi, Ken Kawabata, Keiichi Kanno, Masaki Shimizu
Diagnosis of mitochondrial respiratory chain disorder (MRCD) is often difficult. Its pathogenesis is still unclear. We diagnosed MRCD by measuring the activity of the mitochondrial respiratory chain enzyme, and the patient also had hemophagocytic lymphohistiocytosis (HLH). A preterm female infant was born at 34 weeks of gestation. On day 6, HLH was revealed by bone marrow aspiration. She died on day 10 due to uncontrollable HLH. An autopsy was performed, and we measured the activity of the mitochondrial respiratory chain enzyme in the liver, muscle, and heart...
2016: Case Reports in Pediatrics
Wenwen Wang, Yanqin Yang, Zhewen Xiong, Jiamin Kong, Xinlu Fu, Feihai Shen, Zhiying Huang
Triptolide (TP), a diterpene triepoxide, is a major active component of Tripterygium wilfordii extracts, which are prepared as tablets and has been used clinically for the treatment of inflammation and autoimmune disorders. However, TP's therapeutic potential is limited by severe adverse effects. In a previous study, we reported that TP induced mitochondria dependent apoptosis in cardiomyocytes. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase that plays important roles in the necrosis and apoptosis of cardiomyocytes...
October 14, 2016: Toxicology and Applied Pharmacology
Natalia A Stefanova, Natalia A Muraleva, Kseniya Yi Maksimova, Ekaterina A Rudnitskaya, Elena Kiseleva, Darya V Telegina, Nataliya G Kolosova
Mitochondrial aberrations are observed in human Alzheimer's disease (AD) and in medical conditions that increase the risk of this disorder, suggesting that mitochondrial dysfunction may contribute to pathophysiology of AD. Here, using OXYS rats that simulate key characteristics of sporadic AD, we set out to determine the role of mitochondria in the pathophysiology of this disorder. OXYS rats were treated with a mitochondria-targeted antioxidant SkQ1 from age 12 to 18 months, that is, during active progression of AD-like pathology in these animals...
October 6, 2016: Aging
Nursel Gül, Nuri Yiğit, Fulya Saygılı, Ebru Demirel, Ceren Geniş
We used transmission electron microscopy to examine the cytotoxic effects of the second-generation anticoagulant rodenticides difenacoum and brodifacoum on rat liver. A single dose of difenacoum or brodifacoum was administered to rats by gastric gavage and liver samples were taken after 24 h, four days or seven days. In the livers of rats treated with difenacoum for 24 h, hepatocytes typically showed increased numbers of lysosomes, as well as enlargement of both the perinuclear space and the cisternae of the rough endoplasmic reticulum (RER), while sinusoids were irregularly shaped and contained Kupffer cells...
September 1, 2016: Arhiv za Higijenu Rada i Toksikologiju
Leigh A M Demain, Gerard S Conway, William G Newman
Increasingly, mitochondria are being recognised as having an important role in fertility. Indeed in assisted reproductive technologies mitochondrial function is a key indicator of sperm and oocyte quality. Here, we review the literature regarding mitochondrial genetics and infertility. In many multisystem disorders caused by mitochondrial dysfunction death occurs prior to sexual maturity, or the clinical features are so severe that infertility may be under-reported. Interestingly, many of the genes linked to mitochondrial dysfunction and infertility have roles in the maintenance of mitochondrial DNA or in mitochondrial translation...
October 17, 2016: Clinical Genetics
Francesco Demaria, Franco De Crescenzo, Anna Maria Caramadre, Adele D'Amico, Antonella Diamanti, Fabiana Fattori, Maria Pia Casini, Stefano Vicari
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystemic autosomal recessive disorder mainly caused by mutations in the nuclear gene TYMP, encoding thymidine phosphorylase. It generally appears in childhood and is clinically characterized by severe gastrointestinal dysmotility, cachexia, ptosis, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy on brain magnetic resonance imaging. The disease is clinically heterogeneous with the main symptoms being gastrointestinal, with an important weight loss...
October 12, 2016: Journal of Adolescent Health: Official Publication of the Society for Adolescent Medicine
Hongzheng Dai, Victor Wei Zhang, Ayman W El-Hattab, Can Ficicioglu, Marwan Shinawi, Matthew Lines, Andreas Schulze, Markey McNutt, Garret Gotway, Xia Tian, Stella Chen, Jing Wang, William J Craigen, Lee-Jun Wong
Mutations in FBXL4 have recently been recognized to cause a mitochondrial disorder, with clinical features including early-onset lactic acidosis, hypotonia, and developmental delay. FBXL4 sequence analysis was performed in 808 subjects suspected to have a mitochondrial disorder. In addition, 28 samples from patients with early onset of lactic acidosis, but without identifiable mutations in 192 genes known to cause mitochondrial diseases, were examined for FBXL4 mutations. Definitive diagnosis was made in ten new subjects with a total of seven novel deleterious variants; five null and two missense substitutions...
October 15, 2016: Clinical Genetics
Salvatore Grosso, Maria Alessandra Carluccio, Elena Cardaioli, Alfonso Cerase, Alessandro Malandrini, Chiara Romano, Antonio Federico, Maria Teresa Dotti
BACKGROUND: Complex I deficiency is the most common energy generation disorder which may clinically present at any age with a wide spectrum of symptoms and signs. The T10158C mutation ND3 gene is rare and occurs in patients showing an early rapid neurological deterioration invariably leading to death after a few months. CASE PRESENTATION: We report a 9year-old boy with a mtDNA T10158C mutation showing a mild MELAS-like phenotype and brain MRI features congruent with both MELAS and Leigh syndrome...
October 11, 2016: Brain & Development
Adrienne Wang, Jacob Mouser, Jason Pitt, Daniel Promislow, Matt Kaeberlein
Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS...
October 11, 2016: Oncotarget
Vitaly K Koltover
There are two generally known concepts in biology of aging. Accordingly to the first one, there is a program of aging. The alternative concept advocates that aging proceeds stochastically. In this area of research, free radical-theory of aging, which was put forward by Denham Harman in fifties of XXth century, has determined the most heuristic line. The goal of this review is to demonstrate how the aging program and the aging stochastics are united on the basis of the systems theory of reliability. On this basis, universal features of aging, such as the exponential growth of mortality rate with time and correlation of longevity with the species-specific resting metabolism, are naturally explained...
October 9, 2016: Current Aging Science
Hee Jeong Yoo, Mira Park, Soon Ae Kim
OBJECTIVES: Several reports suggest that mitochondrial dysfunction is involved in the pathophysiology of autism spectrum disorders (ASD). Therefore, mitochondrial DNA (mtDNA) copy number, a common biomarker for mitochondrial dysfunction, might be associated with ASD phenotypes. METHODS: Relative mtDNA copy number in the peripheral blood cells of 100 Korean ASD patients and their unaffected sib-pairs was measured by quantitative polymerase chain reaction (qPCR). RESULTS: ASD patients had significantly higher relative mtDNA copy numbers than their unaffected sibs (P = ...
October 14, 2016: World Journal of Biological Psychiatry
E M Ribe, S Lovestone
As populations across the world both age and become more obese, the numbers of individuals with Alzheimer's disease and diabetes are increasing; posing enormous challenges for society and consequently becoming priorities for governments and global organizations. These issues, an ageing population at risk of neurodegenerative diseases such as Alzheimer's disease and an increasingly obese population at risk of metabolic alterations such as type 2 diabetes, are usually considered as independent conditions, but increasing evidence from both epidemiological and molecular studies link these disorders...
October 14, 2016: Journal of Internal Medicine
Yamilee Hurtado-Roca, Marta Ledesma, Monica Gonzalez-Lazaro, Raquel Moreno-Loshuertos, Patricio Fernandez-Silva, Jose Antonio Enriquez, Martin Laclaustra
Alterations of mitochondrial DNA copy number (mtDNAcn) in the blood (mitochondrial to nuclear DNA ratio) appear associated with several systemic diseases, including primary mitochondrial disorders, carcinogenesis, and hematologic diseases. Measuring mtDNAcn in DNA extracted from whole blood (WB) instead of from peripheral blood mononuclear cells or buffy coat may yield different results due to mitochondrial DNA present in platelets. The aim of this work is to quantify the contribution of platelets to mtDNAcn in whole blood [mtDNAcn(WB)] and to propose a correction formula to estimate leukocytes' mtDNAcn [mtDNAcn(L)] from mtDNAcn(WB)...
2016: PloS One
Kaname Akamata, Jun Wei, Mitra Bhattacharyya, Paul Cheresh, Michael Y Bonner, Jack L Arbiser, Kirtee Raparia, Mahesh P Gupta, David W Kamp, John Varga
Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts...
October 6, 2016: Oncotarget
Ling Zong, Kaitian Chen, Xuan Wu, Min Liu, Hongyan Jiang
OBJECTIVE: Identification of rare deafness genes for inherited congenital sensorineural hearing impairment remains difficult, because a large variety of genes are implicated. In this study we applied targeted capture and next-generation sequencing to uncover the underlying gene in a three-generation Han family segregating recessive inherited hearing loss and retinitis pigmentosa. METHODS: After excluding mutations in common deafness genes GJB2, SLC26A4 and the mitochondrial gene, genomic DNA of the proband of a Han family was subjected to targeted next-generation sequencing...
November 2016: International Journal of Pediatric Otorhinolaryngology
Meredith Meyer, Attila D Kovács, David A Pearce
Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 (-/-) ) mice, a model of infantile CLN1 disease...
October 8, 2016: Metabolic Brain Disease
Santhosh Kumar Sariki, Pushpendra Kumar Sahu, Upendarrao Golla, Vikash Singh, Gajendra Kumar Azad, Raghuvir S Tomar
Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as; redox, unfolded protein response and TOR in the yeastsen1ΔN mutant (N terminal truncation)...
October 8, 2016: FEBS Journal
Mark Lubinsky
An association between congenital malformations and fetal growth restriction (FGR) can be largely explained by a relationship with early embryonic hypocellularity. The malformations include the VACTERL association, which is exceptional as a Mendelian syndrome, but is commonly associated with monozygotic twinning, maternal diabetes, and some forms of aneuploidy, all characterized by a small embryo early in development. Parsimony suggests that these different links to VACTERL are related to the hypocellularity as a single common factor, rather than as an expression of three independent pathogenetic processes...
September 22, 2016: American Journal of Medical Genetics. Part A
Jasmine Chow, Joyeeta Rahman, John C Achermann, Mehul T Dattani, Shamima Rahman
Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves...
October 7, 2016: Nature Reviews. Endocrinology
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