Ferritin is secreted via 2 distinct nonclassical vesicular pathways

Truman-Rosentsvit, Marianna; Berenbaum, Dina; Spektor, Lior; Cohen, Lyora A.; Belizowsky-Moshe, Shirly; Lifshitz, Lena; Ma, Jing; Li, Wei; Kesselman, Ellina; Abutbul-Ionita, Inbal; Danino, Dganit; Gutiérrez, Lucía; Li, Huihui; Li, Kuanyu; Lou, Huifang; Regoni, Maria; Poli, Maura; Glaser, Fabian; Rouault, Tracey A.; Meyron-Holtz, Esther G.

doi:10.1182/blood-2017-02-768580

Cited by 168 publications

(139 citation statements)

References 79 publications

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“…Although serum ferritin is the best biomarker of iron deficiency, the mechanisms of its release as well as its function in the circulation remain mysterious. 22 Iron-restricted erythropoiesis Iron restriction limits the expansion of early erythropoiesis and optimizes iron use by terminal erythropoiesis. In vitro iron deprivation blunts the EPO responsiveness of early progenitors through inactivation of irondependent aconitase, which suppresses isocitrate production.…”

Section: Mechanisms Of Adaptationmentioning

confidence: 99%

Iron deficiency

Camaschella¹

2019

Blood

472

415

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Iron deficiency anemia affects >1.2 billions individuals worldwide, and iron deficiency in the absence of anemia is even more frequent. Total-body (absolute) iron deficiency is caused by physiologically increased iron requirements in children, adolescents, young and pregnant women, by reduced iron intake, or by pathological defective absorption or chronic blood loss. Adaptation to iron deficiency at the tissue level is controlled by iron regulatory proteins to increase iron uptake and retention; at the systemic level, suppression of the iron hormone hepcidin increases iron release to plasma by absorptive enterocytes and recycling macrophages. The diagnosis of absolute iron deficiency is easy unless the condition is masked by inflammatory conditions. All cases of iron deficiency should be assessed for treatment and underlying cause. Special attention is needed in areas endemic for malaria and other infections to avoid worsening of infection by iron treatment. Ongoing efforts aim at optimizing iron salts–based therapy by protocols of administration based on the physiology of hepcidin control and reducing the common adverse effects of oral iron. IV iron, especially last-generation compounds administered at high doses in single infusions, is becoming an effective alternative in an increasing number of conditions because of a more rapid and persistent hematological response and acceptable safety profile. Risks/benefits of the different treatments should be weighed in a personalized therapeutic approach to iron deficiency.

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Section: Mechanisms Of Adaptationmentioning

confidence: 99%

Iron deficiency

Camaschella¹

2019

Blood

472

415

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“…Ferritin is released into serum via non‐classical lysosomal secretory pathways in macrophages, and as such may be used as a marker of macrophage activation . Ferritin is also a well‐established acute phase reactant and non‐specific marker of inflammation .…”

Section: Discussionmentioning

confidence: 99%

“…Ferritin is released into serum via non-classical lysosomal secretory pathways in macrophages, and as such may be used as a marker of macrophage activation. 19,20 Ferritin is also a well-established 22 ; and third, because ferritin, though certainly an exquisite marker of inflammation, is a highly non-specific one. 8 Notably, HLH-2004 reported a sensitivity of 84% for their ferritin cutoff however reported no associated specificity.…”

Section: Discussionmentioning

confidence: 99%

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis

Naymagon

Tremblay

Mascarenhas

2020

European J of Haematology

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Background The standard diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include hyperferritinemia to >500 ng/mL. This ferritin threshold is based on pediatric data, and evidence for its application among adults with secondary HLH is lacking. Objective and Methods We conducted a retrospective study assessing the relationship between extreme hyperferritinemia and adult secondary HLH at our institution. All adult inpatients seen over a 10‐year period, with serum ferritin >5000 ng/mL, were included. Results Among 1055 patients with serum ferritin >5000 ng/mL, there were 69 cases of HLH (HLH prevalence of 6.5%). Mean ferritin among HLH patients was 70 398 ng/mL (SD 122 908), median 40 019 ng/mL (IQR 16 051‐68 326). The prevalence of HLH only reached 50% as serum ferritin approached 90 000 ng/mL. A variety of conditions were contributory to hyperferritinemia, most commonly bacterial sepsis (33%), hematologic malignancy (29%), renal failure (24%), and liver injury (18%). The optimal cutoff ferritin for diagnosis of HLH was 16 000 ng/mL (sensitivity 79.4%, specificity 79.2%, PPV 20.9%, and NPV 98.2%). Conclusions The threshold ferritin levels used in diagnostic criteria for adult secondary HLH are too low to be clinically relevant, and efforts should be undertaken to revise them upward. Similar reappraisals should be taken of the other criteria used to diagnose adult HLH.

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“…Meyron-Holtz and collaborators demonstrated ferritin secretion via two independent pathways: a non-classical secretory-autophagy pathway and a multivesicular-body-exosome pathway [44].…”

Section: Ncoa4 Mediates Ferritin Iron Release To Support Erythropoiesismentioning

confidence: 99%

The Role of NCOA4-Mediated Ferritinophagy in Iron Homeostasis

Santana-Codina¹,

Mancias²

2018

Preprint

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Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes.

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Ferritin is secreted via 2 distinct nonclassical vesicular pathways

Cited by 168 publications

References 79 publications

Iron deficiency

Iron deficiency

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis

The Role of NCOA4-Mediated Ferritinophagy in Iron Homeostasis

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