Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes

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.

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

“…To evaluate whether cardiomyocytes (CMs) may also be affected by pathologic free heme, we treated mouse neonatal CMs with 10 µM heme, in presence of either Hx or Albumin (a low affinity heme-binding protein [17]). …”

“…Hx-heme-treated CMs were protected from heme accumulation, compared to cells treated Being heme a well-known pro-oxidant agent [17], we then evaluated ROS levels in CMs exposed to heme alone or bound to either Hx or albumin. In the presence of Hx-heme complexes, CMs were protected from ROS formation, if compared to CMs treated with either albumin-heme complexes or heme alone ( Figure 1D).…”

“…Under physiologic conditions, heme levels are maintained in plasma at very low concentration (0.2 µmol/L) [17]. However, in pathologic conditions associated with intravascular hemolysis such as hemolytic anemias (i.e.…”

“…However, in pathologic conditions associated with intravascular hemolysis such as hemolytic anemias (i.e. hemoglobinopathies or G6PD deficiency), heme levels rise up to 20-50 µmol/L [17]. Interestingly, β-thalassemia intermedia, a paradigmatic disorder of chronic hemolysis with increased free heme, has been associated with systolic and diastolic dysfunction, leading to the development of heart failure, which is a life-threatening complication in these patients [18].…”

Heme dynamics and trafficking factors revealed by genetically encoded fluorescent heme sensors

“…heme sensors | heme trafficking | heme dynamics | nitric oxide | glyceraldehyde phosphate dehydrogenase H eme (iron protoporphyrin IX) is an essential protein cofactor and signaling molecule (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The canonical view of heme is that it is a static cofactor buried in the active sites of hemoproteins.…”