Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging.
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.
Atamna
Hani
H
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA. hatamna@chori.org
Killilea
David W
DW
Killilea
Alison Nisbet
AN
Ames
Bruce N
BN
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001254:Astrocytoma; D006418:Heme / Q000172:deficiency*; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000648:ultrastructure*; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology*; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D009566:Nitrates; D009573:Nitrites; D006418:Heme; D019001:Nitric Oxide Synthase