Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically

Abstract

Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 μM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective.

Ferroptosis: past, present and future

“…DFO has a certain protective effect on neurons in early PD patients. Huntington's disease (HD) is a progressive neurodegenerative disease, and the continued accumulation of iron and abnormalities in glutamate and GSH levels are typical pathological features of HD 9,64 . The plasma GSH content in HD patients is usually low, and the GPX activity in erythrocytes decreases, which are closely related to ferroptosis 65 .…”

Towards a comprehensive understanding of the contributions of mitochondrial dysfunction and oxidative stress in the pathogenesis and pathophysiology of Huntington's disease

“…Also, melatonin treatment should be strongly recommended for people with a genetic predisposition for HD to correct any possible sleep problems as well as delay the onset and progression of the disease (Kalliolia et al, ). Iron consumption should be strongly avoided as evidence suggests that it acts as a mediator of MtD and elevates OS in both mouse models and human HD (Agrawal, Fox, Thyagarajan, & Fox, ).…”

Dementia associated with disorders of the basal ganglia

“…This is evidenced by studies showing that iron accumulation in the basal ganglia is a common feature of many neurodegenerative diseases and results in both cognitive and motor dysfunction. For example, iron has been found to co‐localize with the insoluble protein aggregates that characterize neurodegenerative diseases such as AD, PD, HD, and DLB (Agrawal, Fox, Thyagarajan, & Fox, ; Joppe, Roser, Maass, & Lingor, ; van Bergen et al, ), suggesting a dysfunction in iron trafficking or metabolism as a cause or consequence of pathology. The heavy iron load in the basal ganglia may explain its increased susceptibility to neurodegeneration, so this represents an important brain region to further examine in this context.…”