Heme Oxygenase-1 as a Novel Metabolic Player

hydrogen donor: oxygen oxidoreductase (í µí»¼-methene hydroxylating, decycliz-ing)) catalyzes the rate limiting the step in the oxidative catabolism of heme to generate biliverdin-IXí µí»¼, which is subsequently converted to bilirubin-IXí µí»¼ by cytosolic NAD(P)H-dependent biliverdin reductase [1]. This reaction, which requires molecular oxygen as well as electrons from NADPH-dependent cytochrome p-450 reductase, liberates the small gas mediator carbon monoxide (CO) and ferrous iron [1]. The constitutive form of this enzyme (HO-2) is expressed highly in neuronal and vascular tissues, whereas the inducible form of this enzyme (HO-1) is recognized as a major stress-inducible protein in mammalian cells [2]. HO-1 induction represents a general inducible response in cells and tissues by a broad range of chemical and physical stress agents [3], and it is transcriptionally regulated in response to these agents primarily by the Keap1–Nrf2 system, a master regulator of the oxidative stress response [4]. The inducible form of HO, heme oxygenase-1 (HO-1), confers protection against oxidative stress conditions in vitro and in vivo [5]. Although the mechanisms of HO-1-dependent cytoprotection remain incompletely understood, accumulating evidence has implicated contributory roles for the products generated from HO activity. Biliverdin and bilirubin are potent antioxidant compounds, whereas iron liberated from HO activity stimulates the production of ferritin, a cytoprotective molecule [6]. Previously regarded as metabolic waste, CO may affect intracellu-lar signaling pathways [7]. Exogenously applied CO can mimic the cytoprotective effects of HO-1 [8], involving the modulation of cellular redox state as well as the regulation of apoptosis, inflammation, and cellular proliferation [9]. In recent years, it has become clear that the HO-1/CO system can potentially impact cellular metabolic pathways. The cardinal example is the clearance of intracellular heme by the catabolic activity of HO-1 [1], leading to the redistribution of cellular iron [6, 10]. In this special issue, we sought to invite papers that explore the novel aspects of the HO-1/CO system with respect to the regulation of metabolic pathways. It is increasingly recognized that the mitochondria, the central energy generating organelle of the cell, can play important roles not only in metabolism but also in the regulation of cellular programs, including apoptosis and inflammation, and that mitochondrial dysfunction may be a key component of human diseases [11]. Recent studies have implicated HO-1/CO as important regulators of mito-chondrial biogenesis and mitochondrial function [12, 13]. The paper by N. Rayamajhi et al., published in this special issue, demonstrates that the natural antioxidant quercetin, …