The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation

Fiorito, Veronica; Allocco, Anna Lucia; Petrillo, Sara; Gazzano, Elena; Torretta, Simone; Marchi, Saverio; Destefanis, Francesca; Pacelli, Consiglia; Audrito, Valentina; Provero, Paolo; Medico, Enzo; Chiabrando, Deborah; Porporato, Paolo E.; Cancelliere, Carlotta; Bardelli, Alberto; Trusolino, Livio; Capitanio, Nazzareno; Deaglio, Silvia; Altruda, Fiorella; Pinton, Paolo; Cardaci, Simone; Riganti, Chiara; Tolosano, Emanuela

doi:10.1016/j.celrep.2021.109252

Cited by 38 publications

(75 citation statements)

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“…In addition, the FLVCR1a-silenced cells also showed decreased levels of ALAS1 compared to controls, while overexpression of FLVCR1 resulted in increased ALAS1 expression, suggesting that elevated heme export plays a role in the maintenance of heme synthesis in these cells, likely resulting in downregulation of the TCA cycle as the TCA intermediate succinyl-CoA is consumed for heme synthesis [19]. FLVCR1 silenced CRC cells show increased OXPHOS and TCA cycle flux compared to controls [19]. Thus, the elevated activities of the heme synthesis-export system in CRC downregulates the TCA cycle and oxidative metabolism and promotes tumor growth [19].…”

Section: Heme Synthesis Export and Catabolism Along With Dietary Heme Intake Play A Role In Pancreatic And Colorectal Cancermentioning

confidence: 97%

“…Heme metabolism, especially HO-1 expression, has been widely reported to be connected with cancers [18]. Notably, the ALAS1-mediated heme synthesis and FLVCR1a-mediated heme export are coupled and control the TCA cycle and OXPHOS [19]. Heme is an essential molecule that is involved in mitochondrial OXPHOS complexes formation [20].…”

Section: Elevated Heme Levels Promote Lung Tumorigenesismentioning

confidence: 99%

“…Colorectal cancer (CRC) has been reported to exhibit altered heme synthesis, export, and catabolism, and is potentially related to dietary heme intake. Heme exporter FLVCR1 is overexpressed in humans and mice CRC cells, and FLVCR1a-silenced cells show slower proliferation [19]. In addition, the FLVCR1a-silenced cells also showed decreased levels of ALAS1 compared to controls, while overexpression of FLVCR1 resulted in increased ALAS1 expression, suggesting that elevated heme export plays a role in the maintenance of heme synthesis in these cells, likely resulting in downregulation of the TCA cycle as the TCA intermediate succinyl-CoA is consumed for heme synthesis [19].…”

Section: Heme Synthesis Export and Catabolism Along With Dietary Heme Intake Play A Role In Pancreatic And Colorectal Cancermentioning

confidence: 99%

“…FLVCR1 silenced CRC cells show increased OXPHOS and TCA cycle flux compared to controls [19]. Thus, the elevated activities of the heme synthesis-export system in CRC downregulates the TCA cycle and oxidative metabolism and promotes tumor growth [19]. Many studies of CRC have also examined the role of dietary heme iron in CRC carcinogenesis.…”

Section: Heme Synthesis Export and Catabolism Along With Dietary Heme Intake Play A Role In Pancreatic And Colorectal Cancermentioning

confidence: 99%

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An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

Wang

Ashrafi

Modareszadeh

et al. 2021

Cancers

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Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer’s disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-β-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.

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Section: Heme Synthesis Export and Catabolism Along With Dietary Heme Intake Play A Role In Pancreatic And Colorectal Cancermentioning

confidence: 97%

Section: Elevated Heme Levels Promote Lung Tumorigenesismentioning

confidence: 99%

Section: Heme Synthesis Export and Catabolism Along With Dietary Heme Intake Play A Role In Pancreatic And Colorectal Cancermentioning

confidence: 99%

Section: Heme Synthesis Export and Catabolism Along With Dietary Heme Intake Play A Role In Pancreatic And Colorectal Cancermentioning

confidence: 99%

See 2 more Smart Citations

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

Wang

Ashrafi

Modareszadeh

et al. 2021

Cancers

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“…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 ]. Heme synthesis starts in mitochondria with the condensation of succinyl-CoA and glycine, a reaction catalyzed by 5-aminolevulinate synthase 1 (ALAS1), the rate-limiting enzyme of the biosynthetic process.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

Self Cite

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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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Freeze‐Thaw Microfluidic System Produces “Themis” Nanocomplex for Cleaning Persisters‐Infected Macrophages and Enhancing Uninfected Macrophages

Su,

Yin,

Zhou

et al. 2024

Advanced Materials

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Macrophages are the primary effectors against potential pathogen infections. They can be “parasitized” by intracellular bacteria, serving as “accomplices”, protecting intracellular bacteria and even switching them to persisters. Here, using a freeze‐thaw strategy‐based microfluidic chip, we created a “Themis” nanocomplex (TNC). The TNC consisted of Lactobacillus reuteri‐derived membrane vesicles, heme, and vancomycin, which cleaned infected macrophages and enhanced uninfected macrophages. In infected macrophages, TNC released heme that led to the reconstruction of the respiratory chain complexes of intracellular persisters, forcing them to regrow. The revived bacteria produced virulence factors that destroyed host macrophages (accomplices), thereby being externalized and becoming vulnerable to immune responses. In uninfected macrophages, TNC upregulated the TCA cycle and oxidative phosphorylation (OXPHOS), contributing to immunoenhancement. The combined effect of TNC of cleaning the accomplice (infected macrophages) and reinforcing uninfected macrophages provides a promising strategy for intracellular bacterial therapy.This article is protected by copyright. All rights reserved

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The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation

Cited by 38 publications

References 65 publications

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

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

Freeze‐Thaw Microfluidic System Produces “Themis” Nanocomplex for Cleaning Persisters‐Infected Macrophages and Enhancing Uninfected Macrophages

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