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Complex I and ATP Content Deficiency in Lymphocytes from Friedreich's Ataxia

Published online by Cambridge University Press:  02 December 2014

Mohammad Mehdi Heidari ,
Massoud Houshmand ,
Saman Hosseinkhani ,
Shahriar Nafissi  and
Mehri Khatami
Mohammad Mehdi Heidari
Affiliation:
Genetic Group, Science School, Tarbiat Modares University
Massoud Houshmand*
Affiliation:
Department of Medical Genetic, National Institute for Genetic Engineering and Biotechnology, Special Medical Center
Saman Hosseinkhani
Affiliation:
Biochemical Group Science School, Tarbiat Modares University
Shahriar Nafissi
Affiliation:
Department of Neurology, Medical Science, Tehran University, Tehran, Iran
Mehri Khatami
Affiliation:
Genetic Group, Science School, Tarbiat Modares University
*
Department of Medical Genetic, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
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Abstract

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Background:

Friedreich's ataxia (FRDA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. A deficiency in the protein frataxin causes this disease. Frataxin deficiency leads to progressive iron accumulation in mitochondria, excessive free radical production and dysfunction of respiratory chain complexes. The expansion (GAA) repeat in the first intron causes decreased frataxin expression by interfering with transcription.

Methods:

Activity of mitochondrial respiratory chain complex I (measured as NADH ferricyanide reductase) and intracellular ATP measurement was performed on lymphocyte of FRDA patients (n=12) and control subjects (n=25).

Results:

Our findings showed that complex I activity and intracellular ATP were significantly reduced (P=0.001) in patients compared with controls and we found strong correlation between complex I activity and intracellular ATP content in FRDA patients (r = 0.93; P<0.002). 8.6 and 9.0 kb deletion in mtDNA was detected in 9 patients out of 12 (75%) by multiplex polymerase chain reaction (PCR) and Southern blot analysis.

Conclusions:

This study suggested that a biochemical defect in complex I activity and ATP production, which may be due to iron accumulation in mitochondria, can be involved in age of onset of FRDA.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 36 , Issue 1 , January 2009 , pp. 26 - 31
Copyright
Copyright © The Canadian Journal of Neurological 2009

References

1.Harding, AE.Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104:589–620.Google Scholar
2.Geffroy, G, Barbeau, A, Breton, G.Clinical description and roentgenologic evaluation of patients with Friedreich’s ataxia. Can J Neurol Sci. 1976;3:279–86.Google Scholar
3.Campuzano, V, Monermini, L, Molto, MD, Pianese, L, Cossee, M, Cavalcanti, F, et al.Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271:1423–7.Google Scholar
4.Cossee, M, Schmitt, M, Campuzano, V, Reutenauer, L, Moutou, C, Mandel, JL, et al.Evolution of the Friedreich’s ataxia trinucleotide repeat expansions: founder effect and permutations. Proc Natl Acad Sci USA. 1997;94:7452–7.Google Scholar
5.Bradley, J, Blake, JC, Chamberlain, S, Thomas, PK, Cooper, JM, Schapira, AHV.Clinical Biochemical and molecular genetic correlations in Friedreich’s ataxia. Hum Mol Genet. 2000;9(2): 275–82.Google Scholar
6.Wilson, RB, Roof, DM.Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet. 1997;16:352–7.CrossRefGoogle ScholarPubMed
7.Ramazzotti, A, Vanmansart, V, Foury, F.Mitochondrial functional interactions between frataxin and Isu1p, the iron-sulfur cluster scafold protein, in Saccharomyces cerevisiae. FEBS Letters. 2004;557:215–20.Google Scholar
8.Foury, F, Talibi, D.Mitochondrial control of iron homeostasis. A genome wide analysis of gene expression in a yeast frataxin deficient mutant. J Biol Chem. 2000;276:762–8.Google Scholar
9.Foury, F, Cazzalini, O.Deletion of the yeast homologue of the human gene associated with Friedreich’s ataxia elicits iron accumulation in mitochondria. FEBS Letters. 1997;411:373–7.Google Scholar
10.Babcock, M, de Silva, D, Oaks, R, Davis-Kaplan, S, Jiralerspong, S, Montermini, L, et al.Regulation of mitochondrial iron accumulation by Yfh1, a putative homolog of frataxin. Science. 1999;276:1709–12.CrossRefGoogle Scholar
11.Cooper, JM, Mann, VM, Krige, D, Schapira, AHV.Human mitochondrial complex I dysfunction. Biochim Biophys Acta. 1992;1101:198–203.Google Scholar
12.Kish, SJ, Bergeron, C, Rajput, A, Dozic, S, Masdrogiacomo, F, Chang, L, et al.Brain cytochrome oxidase in Alzheimers disease. J Neurochem. 1992;59:776–9.Google Scholar
13.Schapira, AHV, Cooper, JM, Dexter, D, Clark, JB, Jenner, P, Marsden, CD.Mitochondrial complex I deficiency in Parkinsons disease. J Neurochem. 1990;54:823–7.CrossRefGoogle Scholar
14.Lu, F, Selak, M, O’Connor, J, Croul, S, Lorenzana, C, Butunoi, C, et al.Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in lesions of multiple sclerosis. J Neurol Sci. 2000;177:95–103.CrossRefGoogle ScholarPubMed
15.Rotig, A, de Lonlay, P, Chretien, D, Foury, F, Koenig, M, Sidi, D, et al.Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17:215–7.CrossRefGoogle ScholarPubMed
16.Stanly, P, Williams, SG.Use of the liquid scintillation spectrometer for determining adenosine triphosphate by the luciferase enzyme. Anal Biochem. 1969;29:381–92.Google Scholar
17.Houshmand, M, Shariat Panahi, SM, Nafisi, S, Soltanzadeh, A, Alkandari, FM.Identification and sizing of GAA trinucleotide repeat expansion, investigation for D-loop variations and mitochondrial deletions in Iranian patients with Friedreich’s ataxia. Mitochondrion. 2006;6:87–93.CrossRefGoogle ScholarPubMed
18.Bradford, MM.A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal Biochem. 1976;72:248–54.Google Scholar
19.Dooijewaard, G, Slater, ES.Steady-state kinetics of high molecular weight (Type-I) NADH dehydrogenase. Biochim Biophys Acta. 1976;440:1–15.CrossRefGoogle ScholarPubMed
20.Hatefi, Y, Hanstein, WG.Interactions of reduced and oxidized triphosphopyridine nucleotides with the electron-transport system of bovine heart mitochondria. Biochemistry. 1973;12:3515–22.CrossRefGoogle ScholarPubMed
21.Pianese, L, Turano, M, Lo Casale, MS, De Biase, I, Giacchetti, M, Ponticelli, A, et al.Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes of Friedreich’s ataxia patients and carriers. J Neurol Neurosurg Psychiatry. 2004;75:1061–3.Google Scholar
22.Campuzano, V, Montermini, L, Lutz, Y, Cova, L, Hindelang, C, Jiralerspong, S, et al.Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet. 1997 6;1771–80.Google Scholar
23.Turano, M, Tammaro, A, De Biase, I, Lo Casale, MS, Ruggiero, G, Monticelli, , et al.3-Nitropropionic acid increases frataxin expression in human lymphoblasts and in transgenic rat PC12 cells. Neurosci Lett. 2003;350:184–6.CrossRefGoogle ScholarPubMed
24.Holt, IJ, Harding, AE, Cooper, JM, Schapira, AH, Toscano, A, Clark, JB, et al.Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989;29:699–710.Google Scholar
25.Yen, TC, Su, JH, King, KL, Wei, YH.Aging-associated 5 kb deletion in human liver mitochondrial DNA. Biochem Biophys Res. 1991;178:124–31.Google Scholar
26.Lee, HC, Wei, YH.Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging. J Formos Med Assoc. 1997;96:770–8.Google Scholar
27.Stehling, O, Elsasser, HP, Bruckel, B, Muhlenhoff, U, Lill, R.Iron—sulfur protein maturation in human cells: evidence for a function of frataxin. Hum Mol Genet. 2004;13(23):3007–15.CrossRefGoogle ScholarPubMed
28.Gonzalez-Cabo, P, Vazquez-Manriue, RP, Garcia-Gimeno, MA, Sanz, P, Palau, F.Frataxin interacts functionally with mitochondrial electron transport chain proteins. Hum Mol Genet. 2005;14(15):2091–8.CrossRefGoogle ScholarPubMed
29.Wei, YH.Oxidative stress and mtDNA mutations in human evolution and disease. Proc Natl Acad Sci. 1998;217:53–63.Google Scholar
30.Garlnad, JM, Halestrap, A.Energy metabolism during apoptois. J Biol Chem. 1997;272:4680–8.Google Scholar
31.Nakamura, N, Wada, Y.Properties of DNA fragmentation activity generated by ATP depletion. Cell Death Differ. 2000;7:477–84.Google Scholar
32.Holmgrena, D, Wahlandera, H, Erikssona, BO, Oldforsb, A, Holmec, E, Tuliniusd, M.Cardiomyopathy in children with mitochondrial disease. Eur Heart J. 2003;24:280–8.Google Scholar
33.Lodi, R, Cooper, JM, Bradley, JL, Manners, D, Styles, P, Taylor, DJ, et al.Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA. 1999;96:11492–5.Google Scholar