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Down-regulation of bioenergetics in a cellular model of Friedreich Ataxia.

Friedreich's ataxia (FRDA), an inherited, progressive neurodegenerative disease, is caused by a reduced expression of the mitochondrial iron-binding protein, frataxin. To study the pathophysiological mechanism of how frataxin deficiency causes the devastating disease, we created a cellular model of FRDA by stably knocking down frataxin in glioma LN428 cell line. The expression level of frataxin in knockdown cell lines was about 25% of that of control. Both OXPHOS and glycolysis were significantly down-regulated in frataxin knockdown cells by ~40%. Reduction in these two bioenergetic pathways reduced steady-state ATP levels by 1.6 fold. Western analysis indicated that Fe/S containing subunits in complex I, II and III were decreased by 1-2 fold in response to frataxin deficiency. Reduced protein levels of these subunits affected the assembly of complexes and the formation of supercomplexes, as observed by Blue- Native Gel Electrophoresis. The activities of aconitase were also reduced by 2 fold in response to frataxin deficiency. PDK1, a protein kinase that phosphorylates and thus inactivates pyruvate dehydrogenase alpha subunit, was more than 2-fold over expressed in frataxin knockdown cells. Thus, at three key steps of respiration, including pyruvate entry into TCA cycle, the TCA cycle and OXPHOS, cells down-regulated their activities in response to frataxin deficiency. We conclude that down-regulation of bioenergetics is an important mechanism for the pathological development ...

Tao Wang * (P1) and Bennett Van Houten (2)

(1) Chemistry and Biochemistry, North Dakota State University, Fargo ND and (2) Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA

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Author:Wang, Tao; Van Houten, Bennett
Publication:Proceedings of the North Dakota Academy of Science
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2016
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