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

  • Mohammad Mehdi Heidari (a1), Massoud Houshmand (a2), Saman Hosseinkhani (a3), Shahriar Nafissi (a4) and Mehri Khatami (a1)...

Abstract

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.

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Copyright

Corresponding author

Department of Medical Genetic, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

References

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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;104:589620.
2.Geffroy, G, Barbeau, A, Breton, G.Clinical description and roentgenologic evaluation of patients with Friedreich’s ataxia. Can J Neurol Sci. 1976;3:27986.
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;271:14237.
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;94:74527.
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): 27582.
6.Wilson, RB, Roof, DM.Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet. 1997;16:3527.
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;557:21520.
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;276:7628.
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;411:3737.
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;276:170912.
11.Cooper, JM, Mann, VM, Krige, D, Schapira, AHV.Human mitochondrial complex I dysfunction. Biochim Biophys Acta. 1992;1101:198203.
12.Kish, SJ, Bergeron, C, Rajput, A, Dozic, S, Masdrogiacomo, F, Chang, L, et al.Brain cytochrome oxidase in Alzheimers disease. J Neurochem. 1992;59:7769.
13.Schapira, AHV, Cooper, JM, Dexter, D, Clark, JB, Jenner, P, Marsden, CD.Mitochondrial complex I deficiency in Parkinsons disease. J Neurochem. 1990;54:8237.
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;177:95103.
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;17:2157.
16.Stanly, P, Williams, SG.Use of the liquid scintillation spectrometer for determining adenosine triphosphate by the luciferase enzyme. Anal Biochem. 1969;29:38192.
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;6:8793.
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;72:24854.
19.Dooijewaard, G, Slater, ES.Steady-state kinetics of high molecular weight (Type-I) NADH dehydrogenase. Biochim Biophys Acta. 1976;440:115.
20.Hatefi, Y, Hanstein, WG.Interactions of reduced and oxidized triphosphopyridine nucleotides with the electron-transport system of bovine heart mitochondria. Biochemistry. 1973;12:351522.
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;75:10613.
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;177180.
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;350:1846.
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;29:699710.
25.Yen, TC, Su, JH, King, KL, Wei, YH.Aging-associated 5 kb deletion in human liver mitochondrial DNA. Biochem Biophys Res. 1991;178:12431.
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;96:7708.
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):300715.
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):20918.
29.Wei, YH.Oxidative stress and mtDNA mutations in human evolution and disease. Proc Natl Acad Sci. 1998;217:5363.
30.Garlnad, JM, Halestrap, A.Energy metabolism during apoptois. J Biol Chem. 1997;272:46808.
31.Nakamura, N, Wada, Y.Properties of DNA fragmentation activity generated by ATP depletion. Cell Death Differ. 2000;7:47784.
32.Holmgrena, D, Wahlandera, H, Erikssona, BO, Oldforsb, A, Holmec, E, Tuliniusd, M.Cardiomyopathy in children with mitochondrial disease. Eur Heart J. 2003;24:2808.
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;96:114925.

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

  • Mohammad Mehdi Heidari (a1), Massoud Houshmand (a2), Saman Hosseinkhani (a3), Shahriar Nafissi (a4) and Mehri Khatami (a1)...

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