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

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.

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

“…Because FLVCR-deleted mice develop iron overload in liver and duodenum, as well as tissue macrophages, by 12 weeks (2) and accumulate iron in renal tubular cells by 9 months, 5 heme trafficking via FLVCR at these sites likely contributes to iron homeostasis (3). Heme export via FLVCR may also provide protection from heme or ferrous iron toxicities in liver and brain, as our observations support emerging hypotheses concerning hepatic (45) and neuronal (46,47) injury.…”

Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment

“…The GFAP.HMOX1 mice also exhibit enhanced astroglial iron deposition (W. Song, H. Zukor, and H. M. Schipper, unpublished observations) akin to earlier observations in HMOX1-transfected glial cultures (Zukor et al, 2009). However, the relevance of this finding to schizophrenia is difficult to gauge in light of controversy whether increases in brain iron reported in human schizophrenia are due to the disease or exposure to neuroleptic medications (Casanova et al, 1992).…”

“…Fixed mouse brains (48 weeks; off Dox) were subdissected into STM, HC, SN/VTA, and nucleus accumbens (NAcc) using an anatomic dissecting microscope and processed for TEM as previously described (Zukor et al, 2009).…”

“…HMOX1 is also induced in the prefrontal cortex of patients with schizophrenia (Prabakaran et al, 2004). In cultured astroglia, HO-1 upregulation by transient transfection of HMOX1 cDNA or stimulation of endogenous HO-1 expression by exposure to diverse stressors promotes intracellular oxidative stress, mitochondrial permeability transition, mitochondrial iron deposition (Schipper, 1999;Song et al, 2006), and macroautophagy (Zukor et al, 2009). In coculture paradigms, glial HO-1 overexpression enhances the vulnerability of nearby neuronal constituents to oxidative insult (Frankel and Schipper, 1999;Song et al, 2007).…”

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

“…Another common intracellular stress that effectively leads to the induction of autophagy is oxidative stress. More recently, it has been demonstrated that oxidative stress activates autophagy in dopaminergic neuronal cell lines and cultured primary astrocytes [46][47][48] . Together, ER stress and oxidative stress may be important mechanisms of autophagy activation in ischemic brain injury.…”