HEME: a neglected player in nociception?

Chiabrando, Deborah; Fiorito, Veronica; Petrillo, Sara; Bertino, Francesca; Tolosano, Emanuela

doi:10.1016/j.neubiorev.2021.01.011

Cited by 9 publications

(13 citation statements)

References 194 publications

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“…Heme, the complex of iron and porphyrin IX, is an essential molecule with an increasingly recognized role in cell energetic metabolism. Heme homeostasis relies on the coordinated activity of enzymes and transporters that modulate heme synthesis, import/export, catabolism, or utilization [ 11 , 12 , 13 , 14 , 15 ]. In this context, heme synthesis and heme export have been shown to be co-regulated processes and constitute a unique functional axis interlinked with pathways related to cell energy production [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Endothelial Heme Dynamics Drive Cancer Cell Metabolism by Shaping the Tumor Microenvironment

et al. 2021

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The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming new blood vessels, ECs support tumor growth. In addition to their angiogenic properties, tumor-associated ECs (TECs) establish a unique vascular niche that actively modulates cancer development by shuttling a selected pattern of factors and metabolites to the CC. The profile of secreted metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Recent evidence highlights the involvement of heme metabolism in the regulation of energy metabolism in TECs. The present study shows that interfering with endothelial heme metabolism by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) in TECs, resulted in enhanced fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies (KBs) accumulation in FLVCR1a-deficient TECs. Finally, the results from this study also demonstrate that TECs-derived KBs can be secreted in the extracellular environment, inducing a metabolic rewiring in the CC. Taken together, these data may contribute to finding new metabolic vulnerabilities for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Endothelial Heme Dynamics Drive Cancer Cell Metabolism by Shaping the Tumor Microenvironment

et al. 2021

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“…Heme is a ubiquitous molecule composed of an atom of iron coordinated by the four-pyrrole ring of protoporphyrin IX, and is also the precursor and degradation product of hemoglobin [ 43 ]. Heme has a variety of roles like co-factor for cytochromes involved in the mitochondrial electron transport chain, oxygen transporters (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…hemoglobin, neuroglobin), heme-using peroxidases (e.g. catalase), and nitric oxide synthases and is associated with oxidative stress and degenerative processes [ 43 , 44 ]. Heme is endogenously synthesized in the mitochondria from succinyl-CoA and glycine and is degraded by Heme oxygenase-1 (HO-1).…”

Section: Discussionmentioning

confidence: 99%

Stage related metabolic profile of synovial fluid in patients with acute flares of knee osteoarthritis

Bocsa

Socaciu

Iancu

et al. 2022

Medicine and Pharmacy Reports

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Background and aim. Osteoarthritis (OA) is the most common joint condition and the leading cause of pain and disability in elderly patients. Currently, there is no biomarker available for the early diagnosis of OA, and limited data is available regarding the molecular basis of progression for OA. For this reason, this study aimed to identify the metabolomic profile of early and late OA using high-performance liquid chromatography coupled with untargeted mass spectrometry (LC-MS). Methods. 31 patients with knee OA and joint effusion were enrolled. Based on Kellgren/Laurence scale, 12 patients were classified as early OA (eOA) and 19 as late OA (lOA). The synovial fluid (SF) was collected and characterized by untargeted LC-MS. Only the metabolites identified in more than 25% of each group were kept for further analysis. Principal component analysis (PCA) enabled the unsupervised clustering of the eOA and lOA groups. Further, for classification, the best three principal components (PCs) were used as input for two machine learning algorithms (random forest and naïve Bayes), which were trained to discriminate between the eOA and lOA groups. Results. 43 metabolites were identified in both eOA and lOA, but after selecting the metabolites present in at least 25% of the patients in each group, the metabolomics analysis yielded a panel of only nine metabolites: four metabolites related to phospholipids (phosphatidylcholine 20:0/18:2 and 18:0/20:2, sphingomyelin, and ceramide), three metabolites belonging to purine metabolites (inosine 5'-phosphate, adenosine thiamine diphosphate, and diadenosine 5',5'-diphosphate), one metabolite was a gonadal steroid hormone (estrone 3-sulfate), and one metabolite represented by heme, with all but ceramide (d18:1/20:0) being enriched in the lOA group. By using as features the best three PCs (PC2, PC8 and PC9), random forest and naïve Bayes machine learning algorithms yielded a classification accuracy of 0.81 and 0.78, respectively. Conclusion. Our LC-MS analysis of SF from patients with eOA and lOA indicates stage-dependent differences, lOA being associated with a perturbed metabolome of phospholipids, purine metabolites, gonadal steroid hormones (estrone 3-sulfate) and a heme molecule. Specific questions need to be answered regarding the biosynthesis and function of these metabolites in osteoarthritic joints, with the aim of developing new relevant biomarkers and therapeutic strategies.

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“…To our knowledge, the potential effects of free hemin (or heme) on the excitability of nociceptive sensory neurons, or on specific ion channels involved in peripheral pain processing have never been reported on. Saying this, Chiabrando and co-workers recently pledged for an increased attention to the yet poorly examined role of hemin as a relevant player in nociception [ 29 ]. The authors mainly referred to recent findings showing that loss-of-function variants of the gene encoding for the heme export protein FLVCR1 (feline leukemia virus subgroup receptor 1) can cause hereditary sensory and autonomic neuropathies with a loss of pain perception [ 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Saying this, Chiabrando and co-workers recently pledged for an increased attention to the yet poorly examined role of hemin as a relevant player in nociception [ 29 ]. The authors mainly referred to recent findings showing that loss-of-function variants of the gene encoding for the heme export protein FLVCR1 (feline leukemia virus subgroup receptor 1) can cause hereditary sensory and autonomic neuropathies with a loss of pain perception [ 29 , 30 , 31 ]. A likely mechanism for this disorder is an accumulation of intracellular heme and a consecutive oxidative stress triggering neurotoxicity and thus sensory denervation [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms Account for In Vitro Activation and Sensitization of TRPV1 by the Porphyrin Hemin

Palmaers

Wiegand

Herzog

et al. 2021

IJMS

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TRPV1 mediates pain occurring during sickling episodes in sickle cell disease (SCD). We examined if hemin, a porphyrin released during intravascular hemolysis modulates TRPV1. Calcium imaging and patch clamp were employed to examine effects of hemin on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1 and TRPA1. Hemin induced a concentration-dependent calcium influx in DRG neurons which was abolished by the unspecific TRP-channel inhibitor ruthenium red. The selective TRPV1-inhibitor BCTC or genetic deletion of TRPV1 only marginally impaired hemin-induced calcium influx in DRG neurons. While hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by BCTC, patch clamp recordings only showed potentiated proton- and heat-evoked currents. This effect was abolished by the PKC-inhibitor chelerythrine chloride and in protein kinase C (PKC)-insensitive TRPV1-mutants. Hemin-induced calcium influx through TRPV1 was only partly PKC-sensitive, but it was abolished by the reducing agent dithiothreitol (DTT). In contrast, hemin-induced potentiation of inward currents was not reduced by DTT. Hemin also induced a redox-dependent calcium influx, but not inward currents on hTRPA1. Our data suggest that hemin induces a PKC-mediated sensitization of TRPV1. However, it also acts as a photosensitizer when exposed to UVA-light used for calcium imaging. The resulting activation of redox-sensitive ion channels such as TRPV1 and TRPA1 may be an in vitro artifact with limited physiological relevance.

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HEME: a neglected player in nociception?

Cited by 9 publications

References 194 publications

Endothelial Heme Dynamics Drive Cancer Cell Metabolism by Shaping the Tumor Microenvironment

Endothelial Heme Dynamics Drive Cancer Cell Metabolism by Shaping the Tumor Microenvironment

Stage related metabolic profile of synovial fluid in patients with acute flares of knee osteoarthritis

Distinct Mechanisms Account for In Vitro Activation and Sensitization of TRPV1 by the Porphyrin Hemin

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