Newly uncovered biochemical and functional aspects of ferritin, 2023, Yanatori et al.

SNT Gatchaman

SNT Gatchaman

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Newly uncovered biochemical and functional aspects of ferritin
Izumi Yanatori; Sohji Nishina; Fumio Kishi; Keisuke Hino

Iron homeostasis is strictly regulated at both the systemic and cellular levels by complex mechanisms because of its indispensability and toxicity. Among the various iron-regulatory proteins, ferritin is the earliest discovered regulator of iron metabolism and is a molecule that safely retains excess intracellular iron in the cores of its shells. Two types of ferritin, cytosolic ferritin and mitochondrial ferritin (FTMT), have been identified in a range of organisms from plants to humans.

FTMT was identified approximately 60 years after the discovery of cytosolic ferritin. Cytosolic ferritin expression is regulated in an iron-responsive manner.
Recently, the molecular mechanisms of iron-dependent degradation of cytosolic ferritin or its secretion into serum have been clarified. FTMT, which shares a high degree of sequence homology with cytosolic ferritin, has distinct functions and is regulated in different ways from cytosolic ferritin. Although knowledge of the physiological role of FTMT is still incomplete, recent studies have shed light on the function and regulation of FTMT. The accumulating biological evidence of both ferritins has made it possible to deepen our knowledge about iron metabolism and its significance in diseases.

In this review, we discuss the biological properties of both ferritins, focusing on their newly uncovered behaviors.

Link | PDF (The FASEB Journal)
 
Iron is an essential element for all organisms and indispensable for oxygen transport, energy production, and DNA synthesis as a cofactor, either in the form of ferrous iron (Fe2+ ), heme, or iron–sulfur clusters, for proteins, including enzymes. The biological importance of iron is largely attributable to its chemical properties as a transitional metal. It readily engages in one-electron oxidation–reduction reactions between its ferric (Fe3+ ) and ferrous states.
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In the cytoplasm, a significant fraction of iron is reduced and can participate in the Fenton reaction, in which ferrous iron catalyzes the formation of dangerous free radicals (hydroxyl radicals) that damage the macromolecular components of cells. Ferrous iron also reacts with lipid peroxides to generate lipid radicals such as LO· and LOO·, which play a critical role in ferroptosis, defined as an iron-catalyzed form of nonapoptotic cell death. Thus, this metal act as a double-edged sword. Consequently, iron homeostasis is strictly regulated at both the systemic and cellular levels by complex mechanisms.
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In this review, we discussed two ferritins, cytosolic ferritin and FTMT, focusing on their newly uncovered behavior. Cytosolic ferritin was first isolated 86 years ago, while FTMT was identified approximately 20 years ago. Nevertheless, the detailed mechanisms underlying their regulation, degradation and secretion into serum remained unknown until recently. Once their mechanisms have become evident, the important roles of NCOA4 in the regulation, degradation and secretion of both ferritins are coming into the spotlight. Further evidence for the role of the NCOA4-ferritin axis in iron homeostasis is expected to accumulate in the near future.
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Just as iron has both the aspects of an essential element and a toxic element for organisms, ferritin is a double-edged sword with respect to its protective role in ferroptosis, which is mediated by cytosolic or mitochondrial ferritin, and its role in signal transduction, by which it induces ferroptosis by secreting ferritin in EVs. As the important roles of ferroptosis in cancer development and progression are increasing, we may need to pay more attention to the relationship between ferritin and ferroptosis.
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In addition, several questions that need to be clarified to reinforce our understanding of iron homeostasis are as follows: Are there other pathways for the degradation or secretion of cytosolic ferritin? How is the cellular localization of FTMT determined? How does FTMT cause a shift of iron from cytosolic ferritin to FTMT? More detailed mechanistic insights into the behavior of cytosolic ferritin and FTMT are expected to help elucidate the complex regulation of iron homeostasis.
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Do you know why people with low iron can raise their ferritin (with iron supplements) to be well in range, then they stop supplementing and their ferritin level immediately starts dropping very quickly? And that can happen over and over again?
 
Others may have a better idea, but this old abstract might offer one explanatory scenario. If there's ongoing blood loss, eg from gut or uterus, and iron supplementation is more than can be used in the production of red blood cells. I don't know if that could apply if there was a problem with normal dietary absorption of iron, rather than blood loss.

From Effect of iron therapy on serum ferritin levels in iron-deficiency anemia (1980, Blood) —

The level of serum ferritin is a reliable indicator of body iron stores. Exceptions include liver disease, malignant diseases, and treatment of iron-deficiency anemia. The latter was noted in iron-deficient infants who showed a rise of serum ferritin to normal levels in the first week of treatment. To evaluate this in adults, 14 patients with iron-deficiency anemia were studied prior to and after beginning treatment with oral ferrous sulfate in standard dose, 300 mg t.i.d., or double dose, 600 mg t.i.d. Serum ferritin was assayed by radioimmunoassay.
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No rise occurred in the first 3 wk in 5 patients treated with standard dose, although hematologic response occurred. With double dose, 7 of 9 showed a ferritin rise in 2 days with return to subnormal levels within 6 days of discontinuing iron. This study indicates that standard treatment of iron deficiency anemia in adults does not cause a rise in serum ferritin until hemoglobin levels are normal. The early rise seen with double dose is most likely due to absorption of iron in excess of utilization for erythropoiesis resulting in temporary storage. When iron is discontinued, stores are rapidly depleted as reflected by the prompt decrease in serum ferritin.
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Arnie Pye said:
Do you know why people with low iron can raise their ferritin (with iron supplements) to be well in range, then they stop supplementing and their ferritin level immediately starts dropping very quickly? And that can happen over and over again?
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My doctor couldn't understand why this occurred either. His response was "where does it go?"

Low ferritin started after getting M.E.
 
Mij said:
My doctor couldn't understand why this occurred either. His response was "where does it go?"
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I expect part of the explanation may be that iron is not simply there to allow oxygen transport in red blood cells — it's needed in cells, including within mitochondria. If mitochondrial function is impaired then that would likely affect the requirements for and handling of iron. Ferritin that's measurable in the serum may no longer be directly correlating with body (intracellular) ferritin and/or iron levels.

From Chemistry and biology of ferritin (2021, Metallomics) —

Iron is an essential element for living systems, where it is crucial for oxygen transport, cellular energy production and importantly can either serve as a cofactor, or catalyst involving enzymatic reactions.
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Ferritin has been characterized as a cytosolic protein, but it is also present in other cell compartments, such as the nucleus, mitochondria, and lysosomes, and a small part of ferritin is located in the serum.
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Mitochondrial ferritin can protect cells against ROS and thus against ferroptosis.
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In addition, specific receptors can take up exogenous ferritin via endocytosis.
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Perhaps ME changes the activity of those receptors, leading to a reduction in measurable serum ferritin.

In iron-depleted conditions, ferritin can be found in lysosomal compartments, more specifically in autophagosomes and autolysosomes during a process called ferritinophagy, which generates labile iron from the ferritin stock.
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Nuclear ferritin can protect DNA by sequestering iron and preventing uncontrolled Fenton chemistry, or by directly binding to DNA. Nuclear ferritin tends to be mainly H-ferritin and not L-ferritin, which may suggest that the role of nuclear ferritin is not merely for iron storage.
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Mitochondrial ferritin is a H-type ferritin, suggesting that its role is not merely for iron storage, but possibly to control the mitochondrial LIP [labile iron pool], required for various metabolic processes.
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Ferritin can also be secreted by cells and be found in the serum, where it comprises mostly of L-ferritin subunits. L-ferritin is mainly involved in iron storage and mineralization. Thus, serum ferritin may carry iron, but not load labile iron that is present outside of the cell.
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It is unknown whether ferritin is secreted in a monomeric or multimeric form. It is also unknown whether iron is bound to ferritin during the secretion process or whether iron can be loaded onto ferritin in the serum, which poses the question to what extent serum ferritin levels are indicative of serum iron concentrations.
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Importantly, a substantial fraction of serum ferritin has been proposed to result from macrophages.
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Perhaps ME upsets macrophage function and affects this.

Diagnostic values showed that serum ferritin is a very powerful indicator for the diagnosis of iron deficiency, being more powerful than red cells or transferrin iron saturation. [...] However, measurements of serum ferritin levels do not provide clues as to whether ferritin is in a monomeric or multimeric form, and in the latter case, if the ferritin shell is empty, fully loaded with iron or in an intermediate state.
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Ferritin levels can give additional information on iron storage, delivery, and inflammation, but it should not be considered as an absolute indicator of iron levels for diagnostic and prognostic purposes.
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DokaGirl said:
Likewise: low ferritin started after developing ME. I wonder what percentage of pwME have this same timing.
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I was first treated for anaemia around the age of 10 or 11. I was tested for it because I got a mouthful of really huge mouth ulcers that turned out to have a secondary, bacterial infection - I couldn't eat or speak and I drooled because I couldn't swallow. The anaemia was found about a year after I'd had two operations just six weeks apart. I don't think I was suffering from ME at that time.

Anaemia is a problem that afflicts multiple people in my extended family, mostly female.

But my poor health and energy has been a lifelong issue, and iron problems have been bound up with that. I don't have a diagnosis of ME, although I think I probably have it. If I do have it it probably wasn't triggered by a virus, I would suspect a genetic iron absorption problem and a pituitary problem.
 
Andy said:
In the analysis of DecodeME questionnaire answers from 2022, 14% of participants reported a co-occuring diagnosis of anaemia.
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I wonder how many of those people thought doctors took their anaemia seriously and treated it for long enough to allow for the patient's levels to become similar to those of healthy people and stay there?

According to this (old - 2010) link each molecule of ferritin holds 4,500 atoms of iron.

https://web.archive.org/web/2013112...files/Content/828895/ST ferritin NOV 2010.pdf

I'm fantasising in the next bit...

If ferritin can exist and not be "full" of iron atoms then perhaps the answer to my earlier question (post #3 above) is that the ferritin test is measuring ferritin that is in any state from "full" to empty". Perhaps something (stopping taking iron supplements?) triggers destruction of the empty ferritin molecules and so the level of ferritin drops.
 
Andy said:
In the analysis of DecodeME questionnaire answers from 2022, 14% of participants reported a co-occuring diagnosis of anaemia.
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Thank you @Andy.

That's interesting.


According to Statistics Canada, 3% of the population has anemia (low hemoglobin):

https://www150.statcan.gc.ca/n1/pub/82-003-x/2012004/article/11742-eng.htm#:~:text=Approximately 3% of Canadians had,iron, but by%



NICE has the exact same statistic:

https://www.nice.org.uk/cks-uk-only#:~:text=In the UK, it is,women have iron deficiency anaemia.


Over 30 years ago, someone I know was very iron deficient, fatigued, couldn't stay awake in the early evenings, was exertion intolerant, had muscle pain, and was out of breath with exertion.

This person was, and is very fit, and healthy.

Their hemoglobin was fine, as was the rest of the iron panel that was done, however, when the patient's request for a ferritin test was followed up on, the result was in the single digits. Iron supplementation and eating MORE beef did the trick.

Low ferritin is where my iron issue shows up; the rest of the iron panels are always fine to quite good, including hemoglobin.
 
@DokaGirl I found this :

  • Anaemia of any cause affects around 30% of the global population.
  • Iron deficiency affects around 1 billion people worldwide, and is the most common cause of anaemia.
    • It is especially prevalent in lower-income regions, such as sub-Saharan Africa, South Asia, and the Caribbean.
  • Iron deficiency anaemia remains a significant problem in the developed world, and has a prevalence of 2–5% among adult men and postmenopausal women.
  • In the UK, it is estimated that 3% of men and 8% of women have iron deficiency anaemia.
    • 57, 000 emergency admissions to UK hospitals each year are due to iron deficiency anaemia.
    • Iron deficiency anaemia is the reason for at least 10% of gastroenterology referrals.
  • During childbearing years, there is a higher incidence of iron deficiency anaemia in women because they lose iron through menstruation and pregnancy.
    • The UK prevalence of iron deficiency anaemia in premenopausal women is up to 12%.
    • The UK prevalence of anaemia is estimated to be 23% in pregnant women.
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Source : https://cks.nice.org.uk/topics/anaemia-iron-deficiency/background-information/prevalence/
Last revised : April 2023
 
My carer aunt has high ferritin and anaemia .
Iron supplementation has made a huge difference to her health which she notices almost immediately when she stops .

ETA anaemia is recent . Previous iron panel was ok .
 
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