The free heme concentration in healthy human erythrocytes

Aich, Anupam; Freundlich, Melissa; Vekilov, Peter G.

doi:10.1016/j.bcmd.2015.09.003

Cited by 49 publications

(43 citation statements)

References 41 publications

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“…In nonerythroid tissue, feedback inhibition by heme negatively regulates ALAS1 transcription [49], translation [50,51], mRNA stability [52], protein stability in the mitochondria [53] and mitochondrial import via the MTS [54] to avoid free heme accumulation and toxicity. In contrast, ALAS2, which operates in erythroid cells that are obligated to make upwards of~80 mM heme or~5 × 10 9 molecules of heme per cell for hemoglobin assembly [55], is not inhibited by heme at any level. ALAS2 synthesis is modulated transcriptionally by GATA-1 and other heme-independent factors [56,57] and downregulated post-transcriptionally by microRNA [58] and iron regulatory proteins (IRPs) [59].…”

Section: Ala Productionmentioning

confidence: 92%

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

Swenson

Moore

Marcero

et al. 2020

Cells

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Heme is a ubiquitous and essential iron containing metallo-organic cofactor required for virtually all aerobic life. Heme synthesis is initiated and completed in mitochondria, followed by certain covalent modifications and/or its delivery to apo-hemoproteins residing throughout the cell. While the biochemical aspects of heme biosynthetic reactions are well understood, the trafficking of newly synthesized heme—a highly reactive and inherently toxic compound—and its subsequent delivery to target proteins remain far from clear. In this review, we summarize current knowledge about heme biosynthesis and trafficking within and outside of the mitochondria.

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Section: Ala Productionmentioning

confidence: 92%

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

Swenson

Moore

Marcero

et al. 2020

Cells

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“…Perforations in the intestinal epithelial layer lead to bleeding in the gut and subsequent translocation of erythrocytes into the gastrointestinal lumen [4]. Hemolysis due to pathophysiological stress occurs, resulting in the release of hemoglobin-bound heme and free heme at the site of damage [5]. Heme, an iron-containing porphyrin, is the most abundant source of iron in the human body and many invading pathogens have evolved mechanisms to utilize this rich metabolic resource [6–10].…”

Section: Introductionmentioning

confidence: 99%

Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection

et al. 2018

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Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing symptoms ranging from infectious diarrhea to fulminant colitis. In the last decade, the number of C. difficile infections has dramatically risen, making it the leading cause of reported hospital acquired infection in the United States. Bacterial toxins produced during C. difficile infection (CDI) damage host epithelial cells, releasing erythrocytes and heme into the gastrointestinal lumen. The reactive nature of heme can lead to toxicity through membrane disruption, membrane protein and lipid oxidation, and DNA damage. Here we demonstrate that C. difficile detoxifies excess heme to achieve full virulence within the gastrointestinal lumen during infection, and that this detoxification occurs through the heme-responsive expression of the heme activated transporter system (HatRT). Heme-dependent transcriptional activation of hatRT was discovered through an RNA-sequencing analysis of C. difficile grown in the presence of a sub-toxic concentration of heme. HatRT is comprised of a TetR family transcriptional regulator (hatR) and a major facilitator superfamily transporter (hatT). Strains inactivated for hatR or hatT are more sensitive to heme toxicity than wild-type. HatR binds heme, which relieves the repression of the hatRT operon, whereas HatT functions as a heme efflux pump. In a murine model of CDI, a strain inactivated for hatT displayed lower pathogenicity in a toxin-independent manner. Taken together, these data suggest that HatR senses intracellular heme concentrations leading to increased expression of the hatRT operon and subsequent heme efflux by HatT during infection. These results describe a mechanism employed by C. difficile to relieve heme toxicity within the host, and set the stage for the development of therapeutic interventions to target this bacterial-specific system.

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“…As a consequence, the concentration and physiological role of LH in biology has been controversial (1, 2). Whereas estimates for the concentration of LH across various cell types have spanned subpicomolar to micromolar quantities (1,2,5,54,55), the use of genetically encoded heme sensors in yeast and various nonerythroid human cells lines has established a consensus range for cytosolic LH that spans 10 -100 nM, representing up to 10% of the total heme concentration (7,56). However, few studies have directly probed the contribution of steady-state LH as a heme source for hemoproteins and heme signaling.…”

Section: Discussionmentioning

confidence: 99%

Heme bioavailability and signaling in response to stress in yeast cells

Hanna

Kim

et al. 2018

Journal of Biological Chemistry

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Protoheme (hereafter referred to as heme) is an essential cellular cofactor and signaling molecule that is also potentially cytotoxic. To mitigate heme toxicity, heme synthesis and degradation are tightly coupled to heme utilization in order to limit the intracellular concentration of "free" heme. Such a model, however, would suggest that a readily accessible steady-state, bioavailable labile heme (LH) pool is not required for supporting heme-dependent processes. Using the yeast as a model and fluorescent heme sensors, site-specific heme chelators, and molecular genetic approaches, we found here that 1) yeast cells preferentially use LH in heme-depleted conditions; 2) sequestration of cytosolic LH suppresses heme signaling; and 3) lead (Pb) stress contributes to a decrease in total heme, but an increase in LH, which correlates with increased heme signaling. We also observed that the proteasome is involved in the regulation of the LH pool and that loss of proteasomal activity sensitizes cells to Pb effects on heme homeostasis. Overall, these findings suggest an important role for LH in supporting heme-dependent functions in yeast physiology.

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The free heme concentration in healthy human erythrocytes

Cited by 49 publications

References 41 publications

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection

Heme bioavailability and signaling in response to stress in yeast cells

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