Heme, a major functional form of
iron in the cell, is synthesized in the mitochondria by
ferrochelatase inserting ferrous
iron into
protoporphyrin IX.
Heme deficiency was induced with
N-methylprotoporphyrin IX, a selective inhibitor of
ferrochelatase, in two human brain cell lines, SHSY5Y (
neuroblastoma) and U373 (
astrocytoma), as well as in rat primary hippocampal neurons.
Heme deficiency in brain cells decreases mitochondrial complex IV, activates
nitric oxide synthase, alters
amyloid precursor
protein, and corrupts
iron and
zinc homeostasis. The metabolic consequences resulting from
heme deficiency seem similar to dysfunctional neurons in patients with
Alzheimer's disease.
Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of
heme in these observations could result from its interaction with
heme regulatory motifs in specific
proteins or secondary to the compromised mitochondria. Common causes of
heme deficiency include aging, deficiency of
iron and
vitamin B6, and exposure to toxic metals such as
aluminum.
Iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus,
heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.