Part 1: Get to Know Iron in the Human Body

This is a multi-part series revisiting the inner workings of iron in the human body to better illustrate, explain and contextualize the potential iron plays in health and disease. Education is the key to informed consumers in the health and wellness space. As I see it, the future of human health is becoming more and more dependent on patient-informed plans of action and less so on the advice of field-specific experts. No one knows our bodies, our experiences and our conditions better than us. Now is the time for us, the human collective, to awaken our dormant mastery and begin to build better health alternatives.

I've chosen iron as the first step. The nutritional resume of iron and the domino effect it has on the inflammatory cascade within the body is both well-recognized in the research and almost entirely ignored clinically. It's up to us to change that.

Part 1 will be dedicated to outlining what exactly iron does in the human body: its inherent qualities, its relationships with the systems it participates in and the foundational role it plays in stabilizing a healthy system.

This is an extension of my initial projects in outlining iron metabolism and its crossover with disease pathology.

More content can be found via my Podcast, Diabetics for Diabetics Radio: https://youtu.be/yKVITGbTwkI My eBook, An Ironclad Cause, also covers these topics in sequence.

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From its earthly origins in the soils to ingestion and incorporation into the tissues of plants and animals grazing the land, iron almost always plays its part in the creation of energy. In the chloroplasts of plants where sunlight is converted to consumable energy, iron is involved in the synthesis of chlorophyll, the green pigment responsible for its function. It can be found in the electron transport chain of those same plants.

For the humans and animals consuming those energy-rich plants, iron retains its energy potential. In humans, ingested iron is absorbed in the lower intestine. It undergoes a series of enzymatic modifications to allow for it to be transported into the blood where it binds to hemoglobin.

80% of all of the iron in our body is bound to hemoglobin. Hemoglobin is the red-tinted protein that gives our blood its red color. This hemoglobin/iron combination acts as the delivery system of oxygen to every cell in the body, picking up freshly inhaled oxygen, carrying through our arteries and capillaries to offload oxygen. This oxygen, of course, is what’s responsible for mitochondrial respiration, the source of energy for each one of our cells.

Needless to say, iron is important.

The iron molecule itself is a potent electron acceptor/donor. For those a few years removed from their high school chemistry class, iron is a transition metal, which means it can easily switch between different oxidation states—primarily Fe²⁺ (ferrous) and Fe³⁺ (ferric). This means it can both give up electrons (donor) and accept electrons (acceptor)—a behavior that makes it essential in:

• Energy production (electron transport chain)

• Oxygen transport (hemoglobin)

• Detoxification reactions (cytochrome enzymes)

• DNA synthesis (ribonucleotide reductase)

In simple terms: Iron is like a flexible handoff point in the body’s electrical system—it helps move energy by passing electrons from one molecule to the next.

Iron is the life of every party it attends. Its energy-building capacity is palpable. Chlorophylls in plants? Boom, energy. Mitochondria feeling down? Here’s an electron chain boost. It quite literally breathes oxygen into the cells of our bodies.

See those iron-sulfur (FeS) clusters? Iron finds itself at the heart of cellular energy production.

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This high degree of utility is what makes iron so “magnetic”. Iron management is highly conserved across almost every single living organism in the world. Everything from single-celled bacteria and deep sea amoebas to elephants and blue whales rely on precise iron metabolism to remain alive and energized.

🔹 1. Essential Across All Domains of Life

Iron is required by:

• Animals (vertebrates & invertebrates)

• Plants

• Fungi

• Bacteria

• Archaea

💡 If an organism uses oxygen, odds are it needs iron to process it.

🔹 2. Conserved Biochemical Roles

Despite vast evolutionary differences, iron performs strikingly similar core functions across kingdoms:

Function	Animals	Plants	Microbes
Electron transport	Mitochondrial ETC (cytochromes, Fe-S)	Chloroplasts & mitochondria	Bacterial ETCs, nitrogen fixation
Oxygen handling	Hemoglobin, myoglobin	Catalase, peroxidase, photosynthesis	Aerobic respiration enzymes
DNA synthesis	Ribonucleotide reductase	Same enzyme conserved	Same, iron-dependent variant
Redox reactions	Cytochrome P450s in detox	Cytochrome b₆f in photosynthesis	Cytochromes in respiration & fermentation
Storage & transport	Ferritin, transferrin, hepcidin	Ferritin-like proteins, phytosiderophores	Siderophores, ferritins, transporters

🧪 Many iron-binding proteins (e.g., ferritin, cytochromes) share deep structural homology across kingdoms.

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🌿 Plants vs. Animals: Iron Strategies Differ, But Principles Persist

In Animals:

• Iron comes from diet (heme & non-heme sources)

• Absorbed in the duodenum, transported via transferrin

• Recycled by macrophages

• Regulated by hepcidin

In Plants:

• Iron is absorbed from soil in the Fe²⁺ or chelated Fe³⁺ form

• Strategies include:

  • Strategy I (non-graminaceous plants): Acidify the rhizosphere, reduce Fe³⁺ to Fe²⁺, absorb via transporters

  • Strategy II (grasses): Secrete phytosiderophores that bind and solubilize Fe³⁺ for uptake

🌾 Plants have evolved powerful iron-mobilizing strategies that echo microbial siderophores—again showing conservation across lineages.

🧠 Evolutionary Insights

• Ancient oxygen-free Earth: Iron was abundant and soluble as Fe²⁺

• With the Great Oxygenation Event, Fe²⁺ became Fe³⁺ (insoluble) → life had to evolve iron-binding proteins to access it

• This pressure led to iron-conservation strategies, such as:

  • Ferritin (storage)

  • Siderophores (scavenging)

  • Electron-transfer chains (iron centers)

🔬 Many of these molecular tools are deeply conserved across evolution, showing up with minor variation in bacteria, fungi, plants, and humans.

🔒 Iron Is Also a Battleground in Host–Pathogen Dynamics

• Plants and animals have both evolved iron-withholding strategies (nutritional immunity) to prevent microbial iron theft.

• Microbes, in turn, evolved iron-stealing mechanisms (siderophores, transferrin-binding proteins).

This iron tug-of-war is conserved across life—a sign of its universal biological importance. From both a host health and pathogenic exposure standpoint, iron control is paramount for life. The human body's iron recycling system is among the most efficient and tightly conserved processes in all of human physiology. It reflects a deep evolutionary priority: iron is too valuable—and too dangerous—to be left to chance.

Our body conserves ~95% of the iron it has. That's remarkable efficiency.

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Iron Recycling: A Masterclass in Biological Efficiency

🔹 The Basics:

• Total iron in the body: ~3–4 grams

• Daily dietary iron absorption: only 1–2 mg/day

• Daily iron needs (for red blood cell production, etc.): ~20–25 mg/day

Note: The daily iron need of the body is NOT indicative of how much we need to consume but rather what is actively being circulated and recirculated for biological function. This semantic oversight is a critical error in the nutritional sciences which has led to chronic over iron consumption.

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Iron-ically (ha!), because of how innately regulated and conserved iron is the human body does not have an active iron excretion system. Losses (via bleeding, skin shedding, menstruation) are passive and minimal.

The team of proteins and enzymes responsible for upholding this incredible retention effort? A formidable crew of iron chaperones, tightly regulating and insulating iron from reacting outside of its specific roles.

Ferritin, transferrin, ferroportin and hepcidin are the body’s major iron chaperones. Lactoferrin and ceruloplasmin make up a secondary means of properly regulating iron.

• Ferritin - “Iron is in” - The protein that binds iron as it’s being stored in the cell. It can also occasionally serve as a transport protein when iron is in circulation. Ferritin-bound iron is soluble and non-toxic.

• Transferrin - “Transferring iron” - A protein of the liver whose main purpose is to transport iron into circulation. This protein is the true taxi of iron within the blood plasma.

• Ferroportin - “Portal for iron” - Lives within the cell membrane and serves as the channel that allows iron to exit cells. It is the only transmembrane protein known that allows offloading of iron.

• Hepcidin is a protein made in the liver that serves as a gatekeeper of iron into and out of the cell. It’s called the “master iron regulator” because of its ability to regulate how much iron is stored versus how much is allowed to enter circulation. It is the air traffic control tower for circulating or grounding iron. Iron doesn’t move unless hepcidin says so.

• Ceruloplasmin is a copper-dependent enzyme responsible for transitioning a reactive Fe+2 molecule into an inert and safe-to-move Fe+3 molecule. It's responsible for maintaining a helath copper-iron balance in the body. It can also serve as an acute-phase antioxidant.

• Lactoferrin is a form of transferrin present in milk and other bodily fluids (saliva, tears, pancreatic secretions etc). It's primary role is binding and transporting iron ions, but also serves the innate immune system as an antibacterial, antiviral, anti-parasitic and anti-cancer agent.

Protective Mechanism	Function
Ferritin	Stores iron safely in cells, keeping it out of trouble
Transferrin	Carries iron in the blood, preventing free radical formation
Ceruloplasmin	Converts Fe²⁺ to Fe³⁺ safely (oxidase activity)
Hepcidin	Master hormone controlling iron absorption and storage
Lactoferrin	Binds iron during infection to keep it from feeding pathogens

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OK, Bowie. So it's highly useful, energetically dense and needs a lot of tools to ensure its being protected and conserved. We know it helps carry oxygen via hemoglobin in the blood. What is iron's full resume?

Iron's utility can be classified in 5 main categories:

1. Red Blood Cell Production & Oxygen Delivery (Hemoglobin System)

~65–70% of total body iron is here

Key Pathways & Intricacies:

• Hemoglobin synthesis in bone marrow:

  • Iron (Fe²⁺) is incorporated into heme, which binds oxygen.

  • Requires vitamin B6, succinyl-CoA, and glycine.

• Erythropoiesis is iron-intensive:

  • ~20–25 mg/day required for red blood cell production, 95% recycled from old cells.

• Reticuloendothelial System (RES):

  • Spleen/liver macrophages break down aged RBCs, recover iron, and pass it to transferrin for reuse.

🔄 This is the most tightly regulated and most iron-demanding system in the body.

2. Iron-Dependent Enzymatic Reactions (Mitochondria & Beyond)

~10–15% of body iron

Key Intracellular Roles:

• Mitochondrial respiration:

  • Iron–sulfur clusters and cytochromes are crucial in the electron transport chain (ETC).

• Krebs Cycle:

  • Aconitase is an iron–sulfur enzyme required for isocitrate conversion.

• DNA synthesis:

  • Ribonucleotide reductase is iron-dependent; essential for cell division.

• Antioxidant enzymes:

  • Catalase (breaks down H₂O₂) and peroxidases require heme iron.

• Drug metabolism:

  • Cytochrome P450 enzymes in the liver use iron to detoxify xenobiotics.

• Myoglobin in muscle:

  • Iron-containing protein that stores and shuttles oxygen in muscle cells.

🧬 These are foundational to cellular respiration, detoxification, redox control, and proliferation.

3. Iron Storage & Redistribution (Liver, Spleen, Bone Marrow)

~15–20% of body iron, dynamic depending on health

Normal Storage:

• Ferritin: main iron-storage protein; buffers excess iron

• Hemosiderin: long-term iron storage (more prevalent in overload)

• Ceruloplasmin: copper-containing enzyme that oxidizes Fe²⁺ to Fe³⁺ for loading onto transferrin

Storage Sites:

• Liver (hepatocytes and Kupffer cells): central depot

• Spleen: stores iron from broken-down RBCs

• Bone marrow: stores iron for future erythropoiesis

• Macrophages: store and recycle iron locally

Dysregulation → Tissue Accumulation:

• In overload or chronic inflammation:

  • Iron deposits in pancreas, heart, brain, joints

  • Promotes fibrosis, calcification, and ROS

🏥 Iron storage is both a nutrient bank and a containment strategy to prevent iron-induced oxidative damage.

4. Iron Loss & Excretion (Minimal but Meaningful)

~1–2 mg/day lost

Excretion Pathways:

• Sloughed enterocytes: iron from intestinal lining is lost as cells are shed

• Menstruation: significant source of iron loss in menstruating individuals

• Sweat: small, but increased with exercise or heat exposure

• Urine: very minimal under normal conditions

• Feces: iron loss from bile, but largely reabsorbed unless malabsorptive disease is present

• Shedding of skin cells and hair

💡 The body has no active iron excretion pathway, which is why absorption and recycling are so tightly controlled.

5. Immunity & Inflammation (Context-Dependent Flux)

Often overlooked but critical

Infections:

• The body withholds iron from pathogens using:

  • Hepcidin (traps iron in cells)

  • Lactoferrin and transferrin (bind free iron)

  • Ferritin (sequesters iron intracellularly)

Inflammation:

• Hepcidin levels rise → ferroportin is degraded → iron gets trapped in macrophages

• Leads to Anemia of Chronic Disease (ACD): iron is present but unavailable

In Cancer:

• Tumors hijack iron for DNA synthesis and proliferation

• Downregulate ferroportin, upregulate transferrin receptors

🧠 Iron is part of the immune signaling toolkit—how the body starves threats, but also how imbalance can fuel chronic disease.

Given iron's energetic qualities and its ease of activation, if it finds itself in an imbalanced environment it can become reactive in a harmful way.

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As we can see, iron is a potent molecule. Highly conserved across all forms of life, it is the unspoken keystone piece in cellular respiration and oxidative phosphorylation. This makes it a highly sought after and protected resource.

But with great power, comes great responsibility. We now know the team of proteins, enzymes and pathways the body uses to both protect its iron sources and insulate itself from its power. All these tools help direct iron with great precision.

What happens when iron finds itself outside of its protective measures? What imbalances drive iron into the open? How does the cell handle these situations?

Part 2 will be dedicated to understanding the dynamics of inflammation and how iron's energetic influence can be weaponized in specific cellular conditions. We'll explore what those conditions are and how exactly iron fits into the inflammatory cascade.