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OXPHOS disease

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https://www.readbyqxmd.com/read/29142257/using-a-quantitative-quadruple-immunofluorescent-assay-to-diagnose-isolated-mitochondrial-complex-i-deficiency
#1
Syeda T Ahmed, Charlotte L Alston, Sila Hopton, Langping He, Iain P Hargreaves, Gavin Falkous, Monika Oláhová, Robert McFarland, Doug M Turnbull, Mariana C Rocha, Robert W Taylor
Isolated Complex I (CI) deficiency is the most commonly observed mitochondrial respiratory chain biochemical defect, affecting the largest OXPHOS component. CI is genetically heterogeneous; pathogenic variants affect one of 38 nuclear-encoded subunits, 7 mitochondrial DNA (mtDNA)-encoded subunits or 14 known CI assembly factors. The laboratory diagnosis relies on the spectrophotometric assay of enzyme activity in mitochondrially-enriched tissue homogenates, requiring at least 50 mg skeletal muscle, as there is no reliable histochemical method for assessing CI activity directly in tissue cryosections...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29132502/transcriptomic-and-proteomic-landscape-of-mitochondrial-dysfunction-reveals-secondary-coenzyme-q-deficiency-in-mammals
#2
Inge Kühl, Maria Miranda, Ilian Atanassov, Irina Kuznetsova, Yvonne Hinze, Arnaud Mourier, Aleksandra Filipovska, Nils-Göran Larsson
Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively...
November 14, 2017: ELife
https://www.readbyqxmd.com/read/29103922/17%C3%AE-estradiol-directly-lowers-mitochondrial-membrane-microviscosity-and-improves-bioenergetic-function-in-skeletal-muscle
#3
Maria J Torres, Kim A Kew, Terence E Ryan, Edward Ross Pennington, Chien-Te Lin, Katherine A Buddo, Amy M Fix, Cheryl A Smith, Laura A Gilliam, Sira Karvinen, Dawn A Lowe, Espen E Spangenburg, Tonya N Zeczycki, Saame Raza Shaikh, P Darrell Neufer
Menopause results in a progressive decline in 17β-estradiol (E2) levels, increased adiposity, decreased insulin sensitivity, and a higher risk for type 2 diabetes. Estrogen therapies can help reverse these effects, but the mechanism(s) by which E2 modulates susceptibility to metabolic disease is not well understood. In young C57BL/6N mice, short-term ovariectomy decreased-whereas E2 therapy restored-mitochondrial respiratory function, cellular redox state (GSH/GSSG), and insulin sensitivity in skeletal muscle...
November 1, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29099651/nutritional-interventions-for-mitochondrial-oxphos-deficiencies-mechanisms-and-model-systems
#4
Adam J Kuszak, Michael Graham Espey, Marni J Falk, Marissa A Holmbeck, Giovanni Manfredi, Gerald S Shadel, Hilary J Vernon, Zarazuela Zolkipli-Cunningham
Multisystem metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are severe and often lethal, conditions. Inborn errors of OXPHOS function are termed primary mitochondrial disorders (PMDs), and the use of nutritional interventions is routine in their supportive management. However, detailed mechanistic understanding and evidence for efficacy and safety of these interventions are limited. Preclinical cellular and animal model systems are important tools to investigate PMD metabolic mechanisms and therapeutic strategies...
November 3, 2017: Annual Review of Pathology
https://www.readbyqxmd.com/read/29093766/generation-and-bioenergetic-profiles-of-cybrids-with-east-asian-mtdna-haplogroups
#5
Huaibin Zhou, Ke Nie, Ruyi Qiu, Jingting Xiong, Xiaoli Shao, Bingqian Wang, Lijun Shen, Jianxin Lyu, Hezhi Fang
Human mitochondrial DNA (mtDNA) variants and haplogroups may contribute to susceptibility to various diseases and pathological conditions, but the underlying mechanisms are not well understood. To address this issue, we established a cytoplasmic hybrid (cybrid) system to investigate the role of mtDNA haplogroups in human disease; specifically, we examined the effects of East Asian mtDNA genetic backgrounds on oxidative phosphorylation (OxPhos). We found that mtDNA single nucleotide polymorphisms such as m.489T>C, m...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29075935/novel-gfm2-variants-associated-with-early-onset-neurological-presentations-of-mitochondrial-disease-and-impaired-expression-of-oxphos-subunits
#6
Ruth I C Glasgow, Kyle Thompson, Inês A Barbosa, Langping He, Charlotte L Alston, Charu Deshpande, Michael A Simpson, Andrew A M Morris, Axel Neu, Ulrike Löbel, Julie Hall, Holger Prokisch, Tobias B Haack, Maja Hempel, Robert McFarland, Robert W Taylor
Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case...
October 26, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29073103/packaging-and-transfer-of-mitochondrial-dna-via-exosomes-regulate-escape-from-dormancy-in-hormonal-therapy-resistant-breast-cancer
#7
Pasquale Sansone, Claudia Savini, Ivana Kurelac, Qing Chang, Laura Benedetta Amato, Antonio Strillacci, Anna Stepanova, Luisa Iommarini, Chiara Mastroleo, Laura Daly, Alexander Galkin, Basant Kumar Thakur, Nadine Soplop, Kunihiro Uryu, Ayuko Hoshinob, Larry Norton, Massimiliano Bonafé, Monica Cricca, Giuseppe Gasparre, David Lyden, Jacqueline Bromberg
The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS)...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29065167/cellular-bioenergetics-is-impaired-in-patients-with-chronic-fatigue-syndrome
#8
Cara Tomas, Audrey Brown, Victoria Strassheim, Joanna Elson, Julia Newton, Philip Manning
Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS. Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients. A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls...
2017: PloS One
https://www.readbyqxmd.com/read/29041825/cathepsin-l-deficiency-results-in-reactive-oxygen-species-ros-accumulation-and-vascular-cells-activation
#9
Guo-Xiang Fu, Alex F Chen, Qiu-Mei Xu, Bei-Bei Han, Gao-Zhong Huang, Yuan Zhong
Recent evidence suggests a link between cathepsin L (CTSL) and vascular diseases. However, its contribution to reactive oxygen species (ROS) homeostasis in the vasculature remains unknown. p66shc is a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals. In this study, we explored the relationship between CTSL and oxidative damage in vasculature and whether the oxidative damage is mediated by p66shc.Carotid arteries from aged mice (24 months old) showed a reduction in CTSL expression compared with young wild-type mice (4 months old)...
October 29, 2017: Free Radical Research
https://www.readbyqxmd.com/read/29026901/dietary-iron-loading-negatively-affects-liver-mitochondrial-function
#10
Chiara Volani, Carolina Doerrier, Egon Demetz, David Haschka, Giuseppe Paglia, Alexandros A Lavdas, Erich Gnaiger, Guenter Weiss
Iron is an essential co-factor for several metabolic processes, including mitochondrial respiration, and mitochondria are the major sites of iron-utilization. Cellular iron homeostasis must be tightly regulated, as intracellular iron deficiency can lead to insufficient energy production, whereas iron overload triggers ROS (reactive oxygen species) formation via the Fenton reaction. So far little is known on how iron imbalances affect mitochondrial function in vivo and the impact of the genotype on that, we studied the effects of dietary iron loading on mitochondrial respiratory capacity in liver by comparing two genetically divergent mouse strains, namely C57BL/6N and FVB mice...
November 15, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28973657/in-vitro-characterization-of-mitochondrial-function-and-structure-in-rat-and-human-cells-with-a-deficiency-of-the-nadh-ubiquinone-oxidoreductase-ndufc2-subunit
#11
Salvatore Raffa, Cristina Scrofani, Sabatino Valente, Andrea Micaloni, Forte Maurizio, Franca Bianchi, Roberta Coluccia, Aron M Geurts, Sebastiano Sciarretta, Massimo Volpe, Maria Rosaria Torrisi, Speranza Rubattu
Ndufc2, a subunit of the NADH:ubiquinone oxidoreductase, plays a key role in the assembly and activity of complex I within the mitochondrial OXPHOS chain. Its deficiency has been shown to be involved in diabetes, cancer and stroke. To improve our knowledge on the mechanisms underlying the increased disease risk due to Ndufc2 reduction, we performed the present in vitro study aimed at the fine characterization of the derangements in mitochondrial structure and function consequent to Ndufc2 deficiency. We found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and PBMC obtained from subjects homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage...
August 30, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28973171/defective-mitochondrial-rrna-methyltransferase-mrm2-causes-melas-like-clinical-syndrome
#12
Caterina Garone, Aaron R D'Souza, Cristina Dallabona, Tiziana Lodi, Pedro Rebelo-Guiomar, Joanna Rorbach, Maria Alice Donati, Elena Procopio, Martino Montomoli, Renzo Guerrini, Massimo Zeviani, Sarah E Calvo, Vamsi K Mootha, Salvatore DiMauro, Ileana Ferrero, Michal Minczuk
Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encephalomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m...
November 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28973153/low-dose-rapamycin-extends-lifespan-in-a-mouse-model-of-mtdna-depletion-syndrome
#13
Stephanie Siegmund, Hua Yang, Rohit Sharma, Martin Javors, Owen Skinner, Vamsi Mootha, Michio Hirano, Eric A Schon
Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism...
September 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28943449/inactivation-of-glycogen-synthase-kinase-3%C3%AE-gsk-3%C3%AE-enhances-skeletal-muscle-oxidative-metabolism
#14
W F Theeuwes, H R Gosker, R C J Langen, K J P Verhees, N A M Pansters, A M W J Schols, A H V Remels
BACKGROUND: Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3β (GSK-3β) represses mitochondrial biogenesis and inhibits PPAR-γ co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3β in the regulation of skeletal muscle oxidative metabolism is unknown...
September 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28942965/biallelic-c1qbp-mutations-cause-severe-neonatal-childhood-or-later-onset-cardiomyopathy-associated-with-combined-respiratory-chain-deficiencies
#15
René G Feichtinger, Monika Oláhová, Yoshihito Kishita, Caterina Garone, Laura S Kremer, Mikako Yagi, Takeshi Uchiumi, Alexis A Jourdain, Kyle Thompson, Aaron R D'Souza, Robert Kopajtich, Charlotte L Alston, Johannes Koch, Wolfgang Sperl, Elisa Mastantuono, Tim M Strom, Saskia B Wortmann, Thomas Meitinger, Germaine Pierre, Patrick F Chinnery, Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers, Salvatore DiMauro, Sarah E Calvo, Vamsi K Mootha, Maurizio Moggio, Monica Sciacco, Giacomo P Comi, Dario Ronchi, Kei Murayama, Akira Ohtake, Pedro Rebelo-Guiomar, Masakazu Kohda, Dongchon Kang, Johannes A Mayr, Robert W Taylor, Yasushi Okazaki, Michal Minczuk, Holger Prokisch
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure...
October 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28906460/a-critical-assessment-of-the-therapeutic-potential-of-resveratrol-supplements-for-treating-mitochondrial-disorders
#16
REVIEW
Boel De Paepe, Rudy Van Coster
In human cells, mitochondria provide the largest part of cellular energy in the form of adenosine triphosphate generated by the process of oxidative phosphorylation (OXPHOS). Impaired OXPHOS activity leads to a heterogeneous group of inherited diseases for which therapeutic options today remain very limited. Potential innovative strategies aim to ameliorate mitochondrial function by increasing the total mitochondrial load of tissues and/or to scavenge the excess of reactive oxygen species generated by OXPHOS malfunctioning...
September 14, 2017: Nutrients
https://www.readbyqxmd.com/read/28905387/management-of-leigh-syndrome-current-status-and-new-insights
#17
REVIEW
Ling Chen, Yu Cui, Dan Jiang, Chui Yan Ma, Hung-Fat Tse, Wuh-Liang Hwu, Qizhou Lian
Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation(OXPHOS) pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in preclinical studies. In this review, we summarize the genetic basis of LS, current treatment, preclinical studies in animal models and the management of other mitochondrial diseases...
September 14, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28903946/ppara-agonist-fenofibrate-enhances-fatty-acid-%C3%AE-oxidation-and-attenuates-polycystic-kidney-and-liver-disease-in-mice
#18
Ronak Lakhia, Matanel Yheskel, Andrea Flaten, Ezekiel B Quittner-Strom, William L Holland, Vishal Patel
PPARA is nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARA and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARA and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARA and FAO/OXPHOS genes is downregulated and in-vivo β-oxidation rate of 3H-labelled triolein is reduced in Pkd1RC/RC mice, a slowly-progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype...
September 13, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28899812/the-starving-brain-overfed-meets-undernourished-in-the-pathology-of-mild-cognitive-impairment-mci-and-alzheimer-s-disease-ad
#19
REVIEW
Kelly J Gibas
Type II Diabetes affects 400 million people worldwide (IDF, 2013). The pathology is paradoxical: internal starvation activated by overfeeding. Hyperinsulinemic impairments of glucose homeostasis are treated with anti-hyperglycemics exacerbating cell starvation, inducing hypoglycemia and raising respiratory quotient. Reductions in hyperglycemia are achieved at the expense of glucose dependency and metabolic inflexibility (Gibas & Gibas, 2017). The brain is not immune from these cycles of starvation. The bioenergetic model characterizes propagation of late-onset, sporadic Alzheimer's disease as loss of molecular fidelity and compromised energy originating in brain networks with highest metabolic demand...
November 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28899396/transcriptomic-meta-analysis-identifies-gene-expression-characteristics-in-various-samples-of-hiv-infected-patients-with-nonprogressive-disease
#20
Le-Le Zhang, Zi-Ning Zhang, Xian Wu, Yong-Jun Jiang, Ya-Jing Fu, Hong Shang
BACKGROUND: A small proportion of HIV-infected patients remain clinically and/or immunologically stable for years, including elite controllers (ECs) who have undetectable viremia (<50 copies/ml) and long-term nonprogressors (LTNPs) who maintain normal CD4(+) T cell counts for prolonged periods (>10 years). However, the mechanism of nonprogression needs to be further resolved. In this study, a transcriptome meta-analysis was performed on nonprogressor and progressor microarray data to identify differential transcriptome pathways and potential biomarkers...
September 12, 2017: Journal of Translational Medicine
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