The sinister face of heme oxygenase-1 in brain aging and disease

Abstract

Under stressful conditions, cellular heme catabolism to carbon monoxide, iron and biliverdin is mediated by the 32 kDa enzyme, heme oxygenase-1 (HO-1). A wide range of pro-oxidant and inflammatory stimuli act on diverse consensus sequences within the Hmox1 promoter to rapidly induce the gene. There is ample evidence attesting to the beneficial effects of HO-1 upregulation in brain. By converting pro-oxidant heme to the antioxidants, biliverdin and bilirubin, HO-1/biliverdin reductase may help restore a more favorable tissue redox microenvironment. Contrariwise, in some cell types and under certain circumstances, heme-derived carbon monoxide and iron may amplify intracellular oxidative stress and exacerbate the disease process. This inimical side of neural HO-1 has often been ignored in biomedical literature promulgating interventions aimed at boosting central HO-1 expression for the management of diverse CNS conditions and is the focus of the current review. A comprehensive model of astroglial stress is presented wherein sustained Hmox1 induction promotes oxidative mitochondrial membrane damage, iron sequestration and mitophagy (macroautophagy). The HO-1 mediated gliopathy renders nearby neuronal constituents vulnerable to oxidative injury and recapitulates 'core' neuropathological features of many aging-related neurodegenerative and some neurodevelopmental brain disorders. A balanced literature should acknowledge that, in a host of chronic human CNS afflictions, the glial HO-1 response may serve as a robust transducer of noxious stimuli, an important driver of relevant neuropathology and a potentially disease-modifying therapeutic target.

Keywords: Aging; Alzheimer disease; Astrocytes; Basal ganglia; Bilirubin; Carbon monoxide; Cerebral hemorrhage; Cerebral infarct; Corpora amylacea; Deferiprone; Dopamine; GABA; GFAP.HMOX1 mice; Glutathione; Gomori; Heme oxygenase-1; Hippocampus; Iron; Locomotor behavior; Macroautophagy; Malaria; Metal; Mild cognitive impairment; Mitochondria; Mitophagy; Multiple sclerosis; Neurodegeneration; Oxidative stress; Oxysterol; Parkinson disease; Prefrontal cortex; Proteasome; Reelin; Schizophrenia; Stereotypy; Sterol; Stroke; Tau; Trauma; Whey protein isolate; microRNA; α-Synuclein; α1-Antitrypsin.