Unraveling the Role of Heme in Neurodegeneration

Abstract

Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Nevertheless, an excess of free-heme promotes oxidative stress and lipid peroxidation, thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid hemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.

The Multifaceted Role of Heme in Cancer

“…Furthermore, nerves influence tumor onset, progression and metastasis formation, mainly through the secretion of neuropeptides and neurotransmitters in TME, where they interact with receptors expressed by cancer cells and by other cells of the TME (131)(132)(133)(134)(135)(136). Heme is required for the survival of different types of neuronal cells (137,138); however, the specific role of heme in the peripheral nervous system and its potential implication in tumor innervation is completely unknown. Several evidences suggest that heme is crucial for the maintenance of the peripheral nervous system, particularly for sensory neurons, one of the types of nerves that actively innervates tumors (139)(140)(141).…”

The Role of Bilirubin and the Other “Yellow Players” in Neurodegenerative Diseases

“…Heme forms a prosthetic group for a variety of hemoproteins, the most important being hemoglobin, myoglobin and cytochromes, and is implicated in multiple cellular functions including energy generation, oxygen transport, defense against increased oxidative stress, cell signaling as well as light-harvesting in higher plants, cyanobacteria and blue-green algae [ 3 ]. As usual, heme might be toxic when surpassing certain threshold concentrations, but may also exert potent protective effects [ 23 ], and this is true also for the CNS [ 12 , 24 , 25 , 26 , 27 ] ( Table 1 and Table 2 ). In cultured neurons, heme accumulates intracellularly and can be even more neurotoxic than iron [ 28 ].…”

“…The heme metabolism in the brain seems to be impaired in neurodegenerative diseases as documented by elevated expression of HMOX1 in these pathologies ([ 29 ], see also below). Simultaneously, hereditary defects of the heme synthesis, cellular export, and import of heme as well as impairment of its incorporation into hemoproteins or heme degradation are associated with specific neurodegenerative disorders supporting the role of heme metabolism in the brain damage [ 24 ]. The role of heme in CNS pathologies is provided by studies on intracranial bleeding demonstrating neurotoxicity of free hemoglobin and its degradation products released during hemorrhage [ 30 ].…”

Interaction between Hemin and Prion Peptides: Binding, Oxidative Reactivity and Aggregation

“…Therefore, several control mechanisms are active for maintaining low concentration of free hemin [ 4 , 5 , 6 ]. Moreover, hemin has also an emerging role in the regulation of several cellular processes in neurons, and therefore, hemin metabolism dysfunctions might contribute to neurodegenerative disorders [ 7 , 8 , 9 ]. For instance, the interaction between hemin and amyloid-β (Aβ) has been found to be relevant for Alzheimer’s disease [ 10 , 11 , 12 , 13 , 14 ].…”