Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

Abstract

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.iron ͉ complex IV ͉ amyloid precursor protein (APP) ͉ nitric oxide synthase ͉ oxidative stress

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

“…4) and DOPA in addition to TMB. We suggest that the oxidation of serotonin by A␤-heme in the presence of H 2 O 2 , which would be produced after the decrease in complex IV (10), is a possible molecular link between A␤ and the abnormal neurotransmitters and oxidative damage seen in AD brain. Peroxidases usually oxidize several organic substrates with minimal selectivity.…”

“…Depleting the regulatory heme by A␤ may also influence additional metabolic functions in addition to those discussed above. The regulatory heme regulates the function of several transcription factors (19,26), soluble guanylate cyclase (41), and metabolic pathways (10,42,43). Thus, it is likely that a decline in the regulatory heme also disturbs specific signaling pathways and gene expression.…”

“…We conclude that this binding causes a decrease in heme-a, which accounts for the decrease in complex IV (10,11), a release of oxidants (11), and the compensatory induction of heme synthesis and iron uptake. We also show that the A␤-heme complex is a peroxidase, that serotonin is a substrate, and that curcumin is an inhibitor.…”

“…Although the molecular link between A␤ and the important cytopathologies seen in AD is not fully understood, our earlier work produced strong evidence that heme may play a key role in the molecular link between A␤ and these cytopathologies. We found that heme metabolism is altered in AD brain (9); that the complex phenotype of heme deficiency (HD) (10,11) overlaps with important cytopathologies in AD (10,11); and that heme binds with A␤, forming an A␤-heme complex (9). We proposed a model in which excessive A␤ in AD brain binds to regulatory heme, creating functional HD (9,12).…”

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

“…Neurodegenerative conditions (e.g., AD) are also characterized by mitochondrial dysfunction and declining complex IV activity (Albers and Beal 2000;Lin and Beal 2006). Selective reduction of complex IV in rat primary hippocampal neurons results in neuronal death (Atamna et al 2002). Whether AD is a specific pathology or simply an extreme manifestation of normal senescence remains debatable .…”