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Mitochondrial disease complex I

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https://www.readbyqxmd.com/read/28070495/an-atypical-presentation-of-acad9-deficiency-diagnosis-by-whole-exome-sequencing-broadens-the-phenotypic-spectrum-and-alters-treatment-approach
#1
H K Aintablian, V Narayanan, N Belnap, K Ramsey, T A Grebe
Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via β-oxidation (He et al. 2007). ACAD9, specifically, is implicated in the processing of palmitoyl-CoA and long-chain unsaturated substrates, but unlike other acyl-CoA dehydrogenases (ACADs), it has a significant role in mitochondrial complex I assembly (Nouws et al. 2010 & 2014). Mutations in this enzyme typically cause mitochondrial complex I deficiency, as well as a mild defect in long chain fatty acid metabolism (Haack et al...
March 2017: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/28070494/pure-myopathy-with-enlarged-mitochondria-associated-to-a-new-mutation-in-mtnd2-gene
#2
Alice Zanolini, Ana Potic, Franco Carrara, Eleonora Lamantea, Daria Diodato, Flavia Blasevich, Silvia Marchet, Marina Mora, Francesco Pallotti, Lucia Morandi, Massimo Zeviani, Costanza Lamperti
To date, only few mutations in the mitochondrial DNA (mtDNA)-encoded ND2 subunit of Complex I have been reported, usually presenting a severe phenotype characterized by early onset encephalomyopathy and early death. In this report, we describe a new mutation in the MTND2 gene in a 21-year-old man with a mild myopathic phenotype characterized by exercise intolerance and increased plasma lactate at rest. Electromyography and brain NMR were normal, and no cardiac involvement was present. Muscle biopsy showed a massive presence of ragged red - COX-positive fibres, with enlarged mitochondria containing osmiophilic inclusions...
March 2017: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/28064324/mitochondrial-iron-sulfur-cluster-biogenesis-from-molecular-understanding-to-clinical-disease
#3
Majid Alfadhel, Marwan Nashabat, Qais Abu Ali, Khalid Hundallah
Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect...
January 2017: Neurosciences: the Official Journal of the Pan Arab Union of Neurological Sciences
https://www.readbyqxmd.com/read/28062948/low-levels-of-prohibitin-in-substantia-nigra-makes-dopaminergic-neurons-vulnerable-in-parkinson-s-disease
#4
Debashis Dutta, Nilufar Ali, Emili Banerjee, Raghavendra Singh, Amit Naskar, Ramesh Kumar Paidi, Kochupurackal P Mohanakumar
Since substantia nigra (SN) and ventral tegmental area (VTA) dopaminergic neurons are, respectively, susceptible or largely unaffected in Parkinson's disease (PD), we searched for protein(s) that regulates this differential sensitivity. Differentially, expressed proteins in SN and VTA were investigated employing two-directional gel electrophoresis- matrix-assisted laser desorption ionization time of flight (MALDI-TOF-TOF) analyses. Prohibitin, which is involved in mitochondrial integrity, was validated using immunoblot, qRT-PCR, and immunohistochemistry in normal mice as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model, PD postmortem human brains, and PD cybrids...
January 6, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28055007/dysfunctional-autophagy-in-rpe-a-contributing-factor-in-age-related-macular-degeneration
#5
Nady Golestaneh, Yi Chu, Yang-Yu Xiao, Gianna L Stoleru, Alexander C Theos
Age-related macular degeneration (AMD) is a devastating neurodegenerative disease and a major cause of blindness in the developed world. Owing to its complexity and the lack of an adequate human model that recapitulates key aspects of the disease, the molecular mechanisms of AMD pathogenesis remain poorly understood. Here we show that cultured human retinal pigment epithelium (RPE) from AMD donors (AMD RPE) are functionally impaired and exhibit distinct phenotypes compared with RPE cultured from normal donors (normal RPE)...
January 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28053619/overexpression-of-n141i-ps2-increases-%C3%AE-secretase-activity-through-up-regulation-of-presenilin-and-pen-2-in-brain-mitochondria-of-nse-hps2m-transgenic-mice
#6
Woo Bin Yun, Jin Ju Park, Ji Eun Kim, Ji Eun Sung, Hyun Ah Lee, Jae Ho Lee, Chang Jun Bae, Dae Youn Hwang
Alzheimer's disease (AD) is known to induce alterations of mitochondrial function such as elevation of oxidative stress and activation of apopotosis. The aim of this study was to investigate the effects of human Presenilin 2 mutant (hPS2m) overexpression on the γ-secretase complex in the mitochondrial fraction. To achieve this, alterations of γ-secretase complex expression and activity were detected in the mitochondrial fraction derived from brains of NSE/hPS2m Tg mice and Non-Tg mice. Herein, the following were observed: i) overexpression of the hPS2m gene significantly up-regulated the deposition of Aβ-42 peptides in the hippocampus and cortex of brain, ii) overexpression of hPS2m protein induced alterations of γ-secretase components such as main component protein and activator protein but not stabilization-related proteins, iii) changes in γ-secretase components induced by overexpression of hPS2m protein up-regulated γ-secretase activity in the mitochondrial fraction, and iv) elevation of γ-secretase activity induced production of Aβ-42 peptides in the mitochondrial fraction...
December 2016: Laboratory Animal Research
https://www.readbyqxmd.com/read/28046125/bgp-15-protects-against-oxidative-stress-or-lipopolysaccharide-induced-mitochondrial-destabilization-and-reduces-mitochondrial-production-of-reactive-oxygen-species
#7
Katalin Sumegi, Katalin Fekete, Csenge Antus, Balazs Debreceni, Eniko Hocsak, Ferenc Gallyas, Balazs Sumegi, Aliz Szabo
Reactive oxygen species (ROS) play a critical role in the progression of mitochondria-related diseases. A novel insulin sensitizer drug candidate, BGP-15, has been shown to have protective effects in several oxidative stress-related diseases in animal and human studies. In this study, we investigated whether the protective effects of BGP-15 are predominantly via preserving mitochondrial integrity and reducing mitochondrial ROS production. BGP-15 was found to accumulate in the mitochondria, protect against ROS-induced mitochondrial depolarization and attenuate ROS-induced mitochondrial ROS production in a cell culture model, and also reduced ROS production predominantly at the complex I-III system in isolated mitochondria...
2017: PloS One
https://www.readbyqxmd.com/read/28035529/hereditary-retinal-dystrophy
#8
Thomas C Hohman
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes...
December 30, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28031252/compound-heterozygosity-for-severe-and-hypomorphic-ndufs2-mutations-cause-non-syndromic-lhon-like-optic-neuropathy
#9
Sylvie Gerber, Martina G Ding, Xavier Gérard, Klaus Zwicker, Xavier Zanlonghi, Marlène Rio, Valérie Serre, Sylvain Hanein, Arnold Munnich, Agnès Rotig, Lucas Bianchi, Patrizia Amati-Bonneau, Orly Elpeleg, Josseline Kaplan, Ulrich Brandt, Jean-Michel Rozet
BACKGROUND: Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin...
December 28, 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28029694/type-i-interferons-mediate-the-neuroinflammatory-response-and-neurotoxicity-induced-by-rotenone
#10
Bevan S Main, Moses Zhang, Kate M Brody, Francis J Kirby, Peter J Crack, Juliet M Taylor
Evidence from post-mortem human brains, animal studies and cell culture models has implicated neuroinflammation in the aetiology of chronic neuropathologies including Alzheimer's and Parkinson's diseases. Although the neuroinflammatory response is considered detrimental in contributing to these pathologies, the underlying mechanisms are still not well understood. The type-I interferons (IFNs) have been well characterised in the periphery and are known to initiate/modulate the immune response. Recently, they have been implicated in aging and we have also demonstrated increased type-I IFN expression in post-mortem human Alzheimer's and Parkinson's disease brains...
December 28, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28008731/mitochondrial-respiratory-chain-complex-i-deficiency-causes-intractable-gastrointestinal-symptoms
#11
Hiroki Kuranobu, Jun Murakami, Naomi Kuranobu, Ken Okamoto, Kei Murayama, Susumu Kanzaki
We report the case of a 13-month-old girl with frequent vomiting, intractable diarrhea, hyperlactatemia, and liver dysfunction. Although the symptoms were treatment resistant, enteral nutrition formula containing medium-chain triglycerides reduced the weight loss, vomiting, and diarrhea. Immunostaining of mitochondrial respiratory chain (MRC) complexes of the colonic mucosa confirmed the diagnosis of MRC complex I deficiency. This case shows that this disease should be included in the differential diagnosis of hyperlactatemia and intractable, cryptogenic gastrointestinal symptoms...
December 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/27997587/cox7a2l-scafi-and-pre-complex-iii-modify-respiratory-chain-supercomplex-formation-in-different-mouse-strains-with-a-bcs1l-mutation
#12
Mina Davoudi, Heike Kotarsky, Eva Hansson, Jukka Kallijärvi, Vineta Fellman
The COX7A2L (Supercomplex Assembly Factor I, SCAFI) protein has been proposed to be a mitochondrial supercomplex assembly factor required for respirasome (supercomplex containing complexes I, III, and IV) formation. In the C57BL/6 mouse strain a homozygous in-frame 6-base-pair deletion in the COX7a2l/SCAF1 gene resulting in unstable protein and suggesting loss of function was previously identified. The loss of SCAFI was shown to impede respirasome formation, a major concern for the use of C57BL mouse strains in mitochondrial research...
2016: PloS One
https://www.readbyqxmd.com/read/27995576/serine-residues-at-positions-162-and-166-of-the-rabies-virus-phosphoprotein-are-critical-for-the-induction-of-oxidative-stress-in-rabies-virus-infection
#13
Wafa Kammouni, Heidi Wood, Alan C Jackson
Our previous work in a mouse model of experimental rabies showed neuronal process (dendrites and axons) degeneration in association with severe clinical disease. Cultured adult rodent dorsal root ganglion (DRG) neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus (RABV) showed axonal swellings and reduced axonal growth with evidence of oxidative stress. We have shown that CVS infection alters a variety of mitochondrial parameters and increases mitochondrial complex I activity and reactive oxygen species (ROS) production...
December 19, 2016: Journal of Neurovirology
https://www.readbyqxmd.com/read/27995398/a-slc39a8-variant-causes-manganese-deficiency-and-glycosylation-and-mitochondrial-disorders
#14
Lisa G Riley, Mark J Cowley, Velimir Gayevskiy, Tony Roscioli, David R Thorburn, Kristina Prelog, Melanie Bahlo, Carolyn M Sue, Shanti Balasubramaniam, John Christodoulou
SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy...
December 19, 2016: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/27986404/mutations-in-mitochondrial-complex-i-assembly-factor-ndufaf3-cause-leigh-syndrome
#15
Fabian Baertling, Laura Sánchez-Caballero, Sharita Timal, Mariël Am van den Brand, Lock Hock Ngu, Felix Distelmaier, Richard Jt Rodenburg, Leo Gj Nijtmans
NDUFAF3 is an assembly factor of mitochondrial respiratory chain complex I. Variants in NDUFAF3 have been identified as a cause of severe multisystem mitochondrial disease. In a patient presenting with Leigh syndrome, which has hitherto not been described as a clinical feature of NDUFAF3 deficiency, we identified a novel homozygous variant and confirmed its pathogenicity in patient fibroblasts studies. Furthermore, we present an analysis of complex I assembly routes representative of each functional module and, thereby, link NDUFAF3 to a specific step in complex I assembly...
December 11, 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27986376/bilateral-upregulation-of-%C3%AE-synuclein-expression-in-the-mouse-substantia-nigra-by-intracranial-rotenone-treatment
#16
Candace H Carriere, Na Hyea Kang, Lennard P Niles
The pesticide rotenone has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopamine neurons along the nigrostriatal pathway, as observed in Parkinson's disease (PD). Recently, intracranial infusion of rotenone was found to increase the protein levels of the Lewy body constituents, α-synuclein and small ubiquitin-related modifier-1(SUMO-1), in the lesioned hemisphere of the mouse brain. These findings are supportive of a mouse model of PD, but information about the dopamine-synthesizing enzyme, tyrosine hydroxylase (TH), an essential marker of dopaminergic status, was not reported...
December 13, 2016: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
https://www.readbyqxmd.com/read/27984680/mitochondrial-activity-in-the-frontal-cortex-area-8-and-angular-gyrus-in-parkinson-s-disease-and-parkinson-s-disease-with-dementia
#17
Paula Garcia-Esparcia, Anusha Koneti, M Cruz Rodríguez-Oroz, Belen Lago, José Antonio Del Rio, Isidro Ferrer
Altered mitochondrial function is characteristic in the substantia nigra in Parkinson's disease (PD). Information about mitochondria in other brain regions such as the cerebral cortex is conflicting mainly because most studies have not contemplated the possibility of variable involvement depending on the region, stage of disease progression, and clinical symptoms such as the presence or absence of dementia. RT-qPCR of 18 nuclear mRNAs encoding subunits of mitochondrial complexes and 12 mRNAs encoding energy metabolism-related enzymes; western blotting of mitochondrial proteins; and analysis of enzymatic activities of complexes I, II, II, IV and V of the respiratory chain were assessed in frontal cortex area 8 and the angular gyrus of middle-aged individuals (MA), and those with incidental PD (iPD), long-lasting PD with parkinsonism without dementia (PD) and long-lasting PD with dementia (PDD)...
December 16, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27979658/sixty-years-old-is-the-breakpoint-of-human-frontal-cortex-aging
#18
Rosanna Cabré, Alba Naudí, Mayelin Dominguez-Gonzalez, Victòria Ayala, Mariona Jové, Natalia Mota-Martorell, Gerard Piñol-Ripoll, Maria Pilar Gil-Villar, Montserrat Rué, Manuel Portero-Otín, Isidre Ferrer, Reinald Pamplona
Human brain aging is the physiological process which underlies as cause of cognitive decline in the elderly and the main risk factor for neurodegenerative diseases such as Alzheimer's disease. Human neurons are functional throughout a healthy adult lifespan, yet the mechanisms that maintain function and protect against neurodegenerative processes during aging are unknown. Here we show that protein oxidative and glycoxidative damage significantly increases during human brain aging, with a breakpoint at 60 years old...
December 13, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27926857/a-lon-clpp-proteolytic-axis-degrades-complex-i-to-extinguish-ros-production-in-depolarized-mitochondria
#19
Kenneth Robert Pryde, Jan Willem Taanman, Anthony Henry Schapira
Mitochondrial dysfunction is implicated in numerous neurodegenerative disorders and in Parkinson's disease (PD) in particular. PINK1 and Parkin gene mutations are causes of autosomal recessive PD, and these respective proteins function cooperatively to degrade depolarized mitochondria (mitophagy). It is widely assumed that impaired mitophagy causes PD, as toxic reactive oxygen species (ROS)-producing mitochondria accumulate and progressively drive neurodegeneration. Instead, we report that a LON-ClpP proteolytic quality control axis extinguishes ROS in depolarized mitochondria by degrading the complex I ROS-generating domain...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27924409/antioxidants-reverse-the-changes-in-energy-metabolism-of-rat-brain-after-chronic-administration-of-l-tyrosine
#20
Brena P Teodorak, Giselli Scaini, Milena Carvalho-Silva, Lara M Gomes, Letícia J Teixeira, Joyce Rebelo, Samira D T De Prá, Neila Zeni, Patrícia F Schuck, Gustavo C Ferreira, Emilio L Streck
Tyrosinemia type II is a rare autosomal recessive disease caused by deficiency of hepatic tyrosine aminotransferase and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that high concentrations of tyrosine provoke mitochondrial dysfunction and oxidative stress, in the present study we investigated the in vivo influence of antioxidants (N-acetylcysteine, NAC; and deferoxamine, DFX) administration on the inhibitory effects on parameters of energy metabolism in cerebral cortex, hippocampus and striatum of rats, provoked by chronic administration of L...
December 6, 2016: Metabolic Brain Disease
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