Can excess activity of a protein in brain support cells cause iron buildup and mitochondrial damage in mice?

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The mechanisms behind pathological iron deposition in the aging and degenerating mammalian central nervous system remain poorly understood. The stress protein HO-1 mediates the breakdown of cellular heme into biliverdin/bilirubin, free iron, and carbon monoxide (CO). HO-1 is upregulated in the brains of people with Alzheimer's disease and Parkinson's disease.

In primary astroglial cultures, inducing HO-1 promotes non-transferrin iron deposition, mitochondrial damage, and macroautophagy, and makes cocultured neuronal elements more susceptible to oxidative injury.

To investigate the role of glial HO-1 in vivo, the researchers used novel conditional GFAP.HMOX1 transgenic mice that selectively overexpress human HO-1 in astrocytes. They examined abnormal brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry, with age-matched wild-type mice as the comparison group.

At 48 weeks, the GFAP.HMOX1 mice had increased glial iron deposits in the hippocampus and other subcortical regions compared with age-matched wild-type animals, without overt changes in iron-regulatory or iron-binding proteins.

Dynamic secondary ion mass spectrometry detected abundant FeO⁻ signals in transgenic mouse brains, but not in wild-type mouse brains. These signals colocalized with degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by transmission electron microscopy (TEM).

The researchers concluded that sustained HO-1 upregulation in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of neural tissues affected by Alzheimer's disease. They proposed that curtailing glial HO-1 hyperactivity may limit iron-mediated cytotoxicity in aging and degenerating neural tissues.