{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:59:39Z","timestamp":1791910779312,"version":"4.3.4"},"reference-count":50,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,8,1]]},"abstract":"<jats:p>FXTAS (fragile X-associated tremor\/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55\u2013200 CGG repeats) in the 5\u2032 untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative\/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.<\/jats:p>","DOI":"10.1042\/bj20091960","type":"journal-article","created":{"date-parts":[[2010,6,1]],"date-time":"2010-06-01T14:24:09Z","timestamp":1275402249000},"page":"545-552","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":154,"title":["Evidence of mitochondrial dysfunction in fragile X-associated tremor\/ataxia syndrome"],"prefix":"10.1042","volume":"429","author":[{"given":"Catherine","family":"Ross-Inta","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicja","family":"Omanska-Klusek","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedrick","family":"Barrow","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Garcia-Arocena","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Iwahashi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Berry-Kravis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, University of Illinois at Chicago, IL 60612, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randi\u00a0J.","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A."},{"name":"M.I.N.D. Institute, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul\u00a0J.","family":"Hagerman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A."},{"name":"M.I.N.D. Institute, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Giulivi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2010,7,14]]},"reference":[{"key":"2021112214473856400_B1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/ajmg.a.31559","article-title":"Neuropathic features in fragile X premutation carriers","volume":"143","author":"Berry-Kravis","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"2021112214473856400_B2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1212\/WNL.57.1.127","article-title":"Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X","volume":"57","author":"Hagerman","year":"2001","journal-title":"Neurology"},{"key":"2021112214473856400_B3","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1086\/374321","article-title":"Fragile X premutation tremor\/ataxia syndrome: molecular, clinical, and neuroimaging correlates","volume":"72","author":"Jacquemont","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"2021112214473856400_B4","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1001\/jama.291.4.460","article-title":"Penetrance of the fragile X-associated tremor\/ataxia syndrome in a premutation carrier population","volume":"291","author":"Jacquemont","year":"2004","journal-title":"JAMA, J. Am. Med. Assoc."},{"key":"2021112214473856400_B5","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1001\/archneurol.2007.30","article-title":"Fragile X-associated tremor\/ataxia syndrome: an aging face of the fragile X gene","volume":"65","author":"Amiri","year":"2008","journal-title":"Arch. Neurol."},{"key":"2021112214473856400_B6","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1093\/brain\/awf184","article-title":"Neuronal intranuclear inclusions in a new cerebellar tremor\/ataxia syndrome among fragile X carriers","volume":"125","author":"Greco","year":"2002","journal-title":"Brain"},{"key":"2021112214473856400_B7","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/brain\/awh683","article-title":"Neuropathology of fragile X-associated tremor\/ataxia syndrome (FXTAS)","volume":"129","author":"Greco","year":"2006","journal-title":"Brain"},{"key":"2021112214473856400_B8","doi-asserted-by":"crossref","first-page":"R83","DOI":"10.1093\/hmg\/ddq166","article-title":"Advances in understanding the molecular basis of FXTAS","volume":"19","author":"Garcia-Arocena","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021112214473856400_B9","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/(SICI)1096-8628(19990402)83:4<322::AID-AJMG17>3.0.CO;2-B","article-title":"Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study \u2013 preliminary data","volume":"83","author":"Allingham-Hawkins","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"2021112214473856400_B10","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/ajmg.1320510419","article-title":"Obstetrical and gynecological complications in fragile X carriers: a multicenter study","volume":"51","author":"Schwartz","year":"1994","journal-title":"Am. J. Med. Genet."},{"key":"2021112214473856400_B11","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/0092-8674(91)90125-I","article-title":"Absence of expression of the FMR-1 gene in fragile X syndrome","volume":"66","author":"Pieretti","year":"1991","journal-title":"Cell"},{"key":"2021112214473856400_B12","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/mrdd.20009","article-title":"Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome","volume":"10","author":"Beckel-Mitchener","year":"2004","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"2021112214473856400_B13","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S0006-291X(02)00682-4","article-title":"FMR1 silencing and the signals to chromatin: a unified model of transcriptional regulation","volume":"295","author":"El-Osta","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112214473856400_B14","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0092-8674(91)90397-H","article-title":"Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome","volume":"65","author":"Verkerk","year":"1991","journal-title":"Cell"},{"key":"2021112214473856400_B15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1093\/hmg\/ddp497","article-title":"Fibroblast phenotype in male carriers of FMR1 premutation alleles","volume":"19","author":"Garcia-Arocena","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021112214473856400_B16","doi-asserted-by":"crossref","first-page":"G1130","DOI":"10.1152\/ajpgi.90545.2008","article-title":"Threonine-deficient diets induced changes in hepatic bioenergetics","volume":"296","author":"Ross-Inta","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021112214473856400_B17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cbpb.2005.05.004","article-title":"Differential requirements of calcium for oxoglutarate dehydrogenase and mitochondrial nitric-oxide synthase under hypoxia: impact on the regulation of mitochondrial oxygen consumption","volume":"142","author":"Solien","year":"2005","journal-title":"Comp. Biochem. Physiol. A Mol. Integr. Physiol."},{"key":"2021112214473856400_B18","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.bbabio.2004.04.015","article-title":"Role of calcium signaling in the activation of mitochondrial nitric oxide synthase and citric acid cycle","volume":"1658","author":"Traaseth","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112214473856400_B19","doi-asserted-by":"crossref","first-page":"H22","DOI":"10.1152\/ajpheart.00766.2003","article-title":"Aspects, mechanism, and biological relevance of mitochondrial protein nitration sustained by mitochondrial nitric oxide synthase","volume":"286","author":"Elfering","year":"2004","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"2021112214473856400_B20","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0140-6736(89)92143-0","article-title":"Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing","volume":"1","author":"Trounce","year":"1989","journal-title":"Lancet"},{"key":"2021112214473856400_B21","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0022-510X(92)90270-U","article-title":"Analyses of mitochondrial respiratory chain function and mitochondrial DNA deletion in human skeletal muscle: effect of ageing","volume":"113","author":"Cooper","year":"1992","journal-title":"J. Neurol. Sci."},{"key":"2021112214473856400_B22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0925-4439(94)90061-2","article-title":"Decline with age of the respiratory chain activity in human skeletal muscle","volume":"1226","author":"Boffoli","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112214473856400_B23","first-page":"65","article-title":"The respiratory chain and oxidative phosphorylation","volume":"17","author":"Chance","year":"1956","journal-title":"Adv. Enzymol. Relat. Subj. Biochem."},{"key":"2021112214473856400_B24","first-page":"535","article-title":"Control of respiration in non-phosphorylating mitochondria is shared between the proton leak and the respiratory chain","volume":"255","author":"Brand","year":"1988","journal-title":"Biochem. J."},{"key":"2021112214473856400_B25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/0076-6879(67)10010-4","article-title":"Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios","volume":"10","author":"Estabrook","year":"1967","journal-title":"Methods Enzymol."},{"key":"2021112214473856400_B26","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/9780470110546.ch6","article-title":"Methods for study of normal and abnormal skeletal muscle mitochondria","volume":"33","author":"Sherratt","year":"1988","journal-title":"Methods Biochem. Anal."},{"key":"2021112214473856400_B27","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/1751120a0","article-title":"A simple and rapid assay of oxidative phosphorylation","volume":"175","author":"Chance","year":"1955","journal-title":"Nature"},{"key":"2021112214473856400_B28","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1007\/s00125-007-0594-3","article-title":"Patients with type\u00a02 diabetes have normal mitochondrial function in skeletal muscle","volume":"50","author":"Boushel","year":"2007","journal-title":"Diabetologia"},{"key":"2021112214473856400_B29","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1002\/mas.20109","article-title":"Current analytical methods for the detection of dityrosine, a biomarker of oxidative stress, in biological samples","volume":"26","author":"DiMarco","year":"2007","journal-title":"Mass Spectrom. Rev."},{"key":"2021112214473856400_B30","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1042\/BJ20090594","article-title":"Nitration of tyrosine residues 368 and 345 in the \u03b2-subunit elicits FoF1-ATPase activity loss","volume":"423","author":"Fujisawa","year":"2009","journal-title":"Biochem. J."},{"key":"2021112214473856400_B31","doi-asserted-by":"crossref","first-page":"E978","DOI":"10.1152\/ajpendo.00739.2009","article-title":"Nitration of specific tyrosines in FoF1 ATP synthase and activity loss in aging","volume":"298","author":"Haynes","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2021112214473856400_B32","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/ng1292-318","article-title":"Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain","volume":"2","author":"Soong","year":"1992","journal-title":"Nat. Genet."},{"key":"2021112214473856400_B33","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/S0076-6879(96)64041-5","article-title":"Use of fibroblast and lymphoblast cultures for detection of respiratory chain defects","volume":"264","author":"Robinson","year":"1996","journal-title":"Methods Enzymol."},{"key":"2021112214473856400_B34","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/brain\/awh650","article-title":"Protein composition of the intranuclear inclusions of FXTAS","volume":"129","author":"Iwahashi","year":"2006","journal-title":"Brain"},{"key":"2021112214473856400_B35","doi-asserted-by":"crossref","first-page":"6211","DOI":"10.1074\/jbc.270.11.6211","article-title":"Activation of the double-stranded RNA-regulated protein kinase by depletion of endoplasmic reticular calcium stores","volume":"270","author":"Prostko","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2021112214473856400_B36","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1749-6632.2002.tb04837.x","article-title":"The unfolded protein response is involved in the pathology of Alzheimer's disease","volume":"977","author":"Kudo","year":"2002","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"2021112214473856400_B37","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1146\/annurev.bi.60.070191.003441","article-title":"Translational control in mammalian cells","volume":"60","author":"Hershey","year":"1991","journal-title":"Annu. Rev. Biochem."},{"key":"2021112214473856400_B38","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/ar.1058","article-title":"Magnetic resonance spectroscopy of the human brain","volume":"265","author":"Ross","year":"2001","journal-title":"Anat. Rec."},{"key":"2021112214473856400_B39","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0968-0004(00)01585-1","article-title":"Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate connection","volume":"25","author":"Rutter","year":"2000","journal-title":"Trends Biochem. Sci."},{"key":"2021112214473856400_B40","doi-asserted-by":"crossref","first-page":"8628","DOI":"10.1523\/JNEUROSCI.20-23-08628.2000","article-title":"Role of Ca2+ stores in metabotropic L-glutamate receptor-mediated supralinear Ca2+ signaling in rat hippocampal neurons","volume":"20","author":"Rae","year":"2000","journal-title":"J. Neurosci."},{"key":"2021112214473856400_B41","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.neuropharm.2006.10.020","article-title":"Group I metabotropic glutamate receptor-induced Ca2+-gradients in rat superficial spinal dorsal horn neurons","volume":"52","author":"Heinke","year":"2007","journal-title":"Neuropharmacology"},{"key":"2021112214473856400_B42","doi-asserted-by":"crossref","first-page":"18953","DOI":"10.1074\/jbc.M109.019141","article-title":"Ca2+\/calmodulin-dependent protein kinase IV links group I metabotropic glutamate receptors to fragile X mental retardation protein in cingulate cortex","volume":"284","author":"Wang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2021112214473856400_B43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1152\/physrev.00004.2004","article-title":"Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons","volume":"85","author":"Verkhratsky","year":"2005","journal-title":"Physiol. Rev."},{"key":"2021112214473856400_B44","doi-asserted-by":"crossref","first-page":"6192","DOI":"10.1074\/jbc.M610643200","article-title":"Rapid turnover of mcl-1 couples translation to cell survival and apoptosis","volume":"282","author":"Adams","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021112214473856400_B45","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1006\/abbi.1994.1245","article-title":"Exposure of hydrophobic moieties promotes the selective degradation of hydrogen peroxide-modified hemoglobin by the multicatalytic proteinase complex, proteasome","volume":"311","author":"Giulivi","year":"1994","journal-title":"Arch. Biochem. Biophys."},{"key":"2021112214473856400_B46","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1097\/00004583-199011000-00007","article-title":"Fragile X syndrome, DSM-III-R, and autism","volume":"29","author":"Reiss","year":"1990","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"2021112214473856400_B47","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1023\/A:1026000404855","article-title":"Autism: the point of view from fragile X studies","volume":"28","author":"Feinstein","year":"1998","journal-title":"J. Autism Dev. Disord."},{"key":"2021112214473856400_B48","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0896-6273(03)00034-5","article-title":"RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice","volume":"37","author":"Miyashiro","year":"2003","journal-title":"Neuron"},{"key":"2021112214473856400_B49","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1399-0004.2009.01275.x","article-title":"Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism","volume":"76","author":"Loesch","year":"2009","journal-title":"Clin. Genet."},{"key":"2021112214473856400_B50","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.genhosppsych.2007.03.003","article-title":"Cognitive, anxiety and mood disorders in the fragile X-associated tremor\/ataxia syndrome","volume":"29","author":"Bourgeois","year":"2007","journal-title":"Gen. Hosp. Psychiatry"}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/429\/3\/545\/665408\/bj4290545.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/429\/3\/545\/665408\/bj4290545.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T05:09:47Z","timestamp":1711516187000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/429\/3\/545\/45536\/Evidence-of-mitochondrial-dysfunction-in-fragile-X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,7,14]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2010,8,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20091960","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,7,14]]}}}