HO‐1‐mediated macroautophagy: a mechanism for unregulated iron deposition in aging and degenerating neural tissues

H Zukor, W Song, A Liberman, J Mui… - Journal of …, 2009 - Wiley Online Library
H Zukor, W Song, A Liberman, J Mui, H Vali, C Fillebeen, K Pantopoulos, TD Wu…
Journal of neurochemistry, 2009Wiley Online Library
J. Neurochem.(2009) 109, 776–791. Abstract Oxidative stress, deposition of non‐transferrin
iron, and mitochondrial insufficiency occur in the brains of patients with Alzheimer disease
(AD) and Parkinson disease (PD). We previously demonstrated that heme oxygenase‐1 (HO‐
1) is up‐regulated in AD and PD brain and promotes the accumulation of non‐transferrin
iron in astroglial mitochondria. Herein, dynamic secondary ion mass spectrometry (SIMS)
and other techniques were employed to ascertain (i) the impact of HO‐1 over‐expression on …
J. Neurochem. (2009) 109, 776–791.
Abstract
Oxidative stress, deposition of non‐transferrin iron, and mitochondrial insufficiency occur in the brains of patients with Alzheimer disease (AD) and Parkinson disease (PD). We previously demonstrated that heme oxygenase‐1 (HO‐1) is up‐regulated in AD and PD brain and promotes the accumulation of non‐transferrin iron in astroglial mitochondria. Herein, dynamic secondary ion mass spectrometry (SIMS) and other techniques were employed to ascertain (i) the impact of HO‐1 over‐expression on astroglial mitochondrial morphology in vitro, (ii) the topography of aberrant iron sequestration in astrocytes over‐expressing HO‐1, and (iii) the role of iron regulatory proteins (IRP) in HO‐1‐mediated iron deposition. Astroglial hHO‐1 over‐expression induced cytoplasmic vacuolation, mitochondrial membrane damage, and macroautophagy. HO‐1 promoted trapping of redox‐active iron and sulfur within many cytopathological profiles without impacting ferroportin, transferrin receptor, ferritin, and IRP2 protein levels or IRP1 activity. Thus, HO‐1 activity promotes mitochondrial macroautophagy and sequestration of redox‐active iron in astroglia independently of classical iron mobilization pathways. Glial HO‐1 may be a rational therapeutic target in AD, PD, and other human CNS conditions characterized by the unregulated deposition of brain iron.
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