Abstract
Heme (iron-protoporphyrin IX) is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing. However, excess free-heme is highly toxic due to its ability to promote oxidative stress and lipid peroxidation, thus leading to membrane injury and, ultimately, apoptosis. Thus, heme metabolism needs to be finely regulated. Intracellular heme amount is controlled at multiple levels: synthesis, utilization by hemoproteins, degradation and both intracellular and intercellular trafficking. This review focuses on recent findings highlighting the importance of controlling intracellular heme levels to counteract heme-induced oxidative stress. The contributions of heme scavenging from the extracellular environment, heme synthesis and incorporation into hemoproteins, heme catabolism and heme transport in maintaining adequate intracellular heme content are discussed. Particular attention is put on the recently described mechanisms of heme trafficking through the plasma membrane mediated by specific heme importers and exporters. Finally, the involvement of genes orchestrating heme metabolism in several pathological conditions is illustrated and new therapeutic approaches aimed at controlling heme metabolism are discussed.
Highlights
Heme is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing
The expression as well as the activity of cytochromes P450 was reduced. These findings indicate that FLVCR1a-mediated heme export is crucial to control intracellular heme levels that in turn regulate heme synthesis, determining cytochrome function in the liver (Vinchi et al, 2014)
Mutations in the uroporphyrinogen synthase (UROS) gene cause the third form of erythropoietic protoporphyria, called congenital erythropoietic protoporphyria (CEP; OMIM: #263700); the partial loss of UROS activity leads to the incomplete metabolism of hydroxymethylbilane and the accumulation of non-physiologic porphyrin isomers in the bone marrow, erythrocytes, urine and other organs
Summary
In contrast to the positive functions of heme, free heme excess can cause cell damage and tissue injury since heme catalyzes the formation of reactive oxygen species (ROS), resulting in oxidative stress. Due to its lipophilic nature, heme may initially lodge within the hydrophobic phospholipid bilayer Within this highly oxidizable matrix, iron catalyzes the oxidation of cell membrane and promotes the formation of cytotoxic lipid peroxide, which enhances membrane permeability, promoting cell lysis and death (Balla et al, 1991; Ryter and Tyrrell, 2000; Kumar and Bandyopadhyay, 2005; Tolosano et al, 2010). The cellular free heme pool may increase after extracellular heme overload, increased heme synthesis, accelerated hemoprotein breakdown, impaired incorporation into apo-hemoproteins, or impaired HO activity, resulting in ROS formation, oxidative damage and cell injury. The acute phase response is a complex systemic early-defence system activated by trauma, infection, stress, neoplasia, and inflammation Most of these stimuli, in particular hemolytic stress and inflammatory stimuli, induce Hx synthesis (Tolosano and Altruda, 2002).
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