HO-1-mediated macroautophagy: a mechanism for unregulated iron deposition in aging and degenerating neural tissues.
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.
Zukor
Hillel
H
Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Song
Wei
W
Liberman
Adrienne
A
Mui
Jeannie
J
Vali
Hojatollah
H
Fillebeen
Carine
C
Pantopoulos
Kostas
K
Wu
Ting-Di
TD
Guerquin-Kern
Jean-Luc
JL
Schipper
Hyman M
HM
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005290:Ferric Compounds / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008652:Mesoporphyrins / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018629:Spectrometry, Mass, Secondary Ion / Q000379:methods; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
D005290:Ferric Compounds; D008652:Mesoporphyrins; C031468:mesoporphyrin IX; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1