Heme Oxygenase in Physiology and Pathology

Dear Colleagues,

Heme oxygenase (HO) catalyzes the rate-limiting step of heme degradation, yielding carbon monoxide (CO), ferrous iron (Fe²⁺), and biliverdin. In mammalian tissues, the HO reaction product biliverdin is further reduced to bilirubin by biliverdin reductase. The mechanism of heme cleavage is evolutionarily conserved and essential for various cellular processes in nearly all living organisms. In plants, enzymatic heme degradation serves for the synthesis of chromophores of photoreceptors, while many microorganisms and animals use HO for iron acquisition from heme. Mammalian heme oxygenase exists in three isoforms, of which only two are catalytically active—the inducible isoform HO-1 and the constitutively expressed isoform HO-2. Various pathophysiological stimuli, such as heme, oxidative stress, hypoxia, and inflammation, induce HO-1 via multiple response elements in the HO-1 promoter region. Both enzymes contribute to the overall HO activity, which is not only required for iron redistribution within the organism, and to maintain homeostasis of heme-proteins. Most importantly, HO activity provides cytoprotection, predominantly by two synergistic effects—the removal of heme, which exerts pro-oxidative effects when in excess, and the generation of the HO products, CO and biliverdin/bilirubin, which possess potent anti-oxidative, anti-apoptotic, and anti-inflammatory properties. Further, both metabolites play important roles as signaling molecules.

Moreover, recent findings show that HO may exert functions not related to its enzymatic activity, such as the formation of protein-protein interactions and involvement in signaling events. Although anchored to the membrane of the endoplasmic reticulum, certain pathophysiological conditions may lead to translocation of a truncated HO isoform to the nuclear compartment, where it can activate stress-associated nuclear transcription factors and DNA repair mechanisms.

However, dysregulated HO may unfold unfavorable effects and contribute to tissue injury, neurodegeneration, and carcinogenesis. Therefore, therapeutic approaches targeting the HO system are promising strategies to restore homeostasis and to support tissue repair. However, many questions related to the different roles of HO isoforms and to their newly discovered functions in physiology and pathology still remain open.

This Special Issue invites methodological approaches, research papers, or reviews that present new findings or concepts on the roles and functions of HO enzymes and their reaction products in animal and plant physiology. Suitable topics include (but are not limited to): structure, function, and regulation of HO in different species; the role of HO and its products in physiological and pathological conditions modulating cell metabolism, signaling, and cell cycle; epigenetic regulation; repair function; and the control of oxidative stress. 

Dr. J. Catharina Duvigneau
Guest Editor

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