Mitochondrial iron dysregulation in Huntington's disease models
Sonal Agrawal,1 Julia A. Fox1, Baskaran Thyagarajan2, and Jonathan H. Fox1 1Department of Veterinary Sciences and 2School of Pharmacy, University of Wyoming, Laramie, WY 82070, USA
Huntington's disease (HD) is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene. Mitochondria are involved in HD pathogenesis and are also a major site of iron utilization and homeostasis. Brain iron dysregulation is involved in the pathogenesis of HD. We investigated a role for mitochondrial iron dysregulation in disease pathogenesis. Using brain regional sub-cellular fractionation and ICP-MS measurements for total iron, in R6/2 and YAC128 mouse models of human HD, we demonstrate that brain iron accumulation is present in mitochondrial enriched, but not cytoplasmic fractions. To investigate potential mechanisms of mitochondrial iron accumulation in HD models we completed Western blot analyses of the mitochondrial iron homeostatic proteins mitoferrin 2, ABCB8 and frataxin in R6/2 mice and in human HD brain. Levels of the iron-uptake protein mitoferrin 2 were increased in R6/2 striatum and cortex and in human HD BA9 and BA17 neocortical regions. Levels of the mitochondrial iron export ABCB8 protein were unaltered in R6/2 mice. Levels of frataxin, a protein involved in iron-sulfur cluster synthesis, were decreased in R6/2 striatum and cortex and human HD BA4 and BA9 neocortical regions. We further demonstrate that mitochondria enriched from R6/2 mouse brain have decreased oxygen uptake compared to controls, and that the lipophilic iron-selective chelator deferiprone restores uptake rates in ex-vivo preparations. Findings support a role of iron as a mediator of functional changes in mouse HD mitochondria. Funding support: NIH-NINDS NS079450
Credits: None available.
You must be logged in and own this product in order to post comments.