Hemoglobin is the protein inside red blood cells responsible for picking up oxygen in the lungs and delivering it to tissues throughout the body. Understanding how it binds and releases oxygen, and what factors shift that balance, is central to understanding respiratory physiology.

Hemoglobin's oxygen binding mechanism

Hemoglobin is a globular protein made of four subunits, each containing a heme group with an iron atom at its center. Each iron atom can reversibly bind one oxygen molecule, so a single hemoglobin can carry up to four $O_2$ molecules.

Whether hemoglobin holds onto or releases oxygen depends on the partial pressure of oxygen ( $pO_2$ ) in the surrounding environment:

In the lungs, $pO_2$ is high (~100 mmHg), so hemoglobin readily binds oxygen.
In the tissues, $pO_2$ is lower (~40 mmHg in resting tissue, even lower during exercise), so hemoglobin releases oxygen, allowing it to diffuse into cells.

Cooperative binding is what makes hemoglobin so efficient. When the first $O_2$ binds to one subunit, it changes the shape of the protein and increases the affinity of the remaining subunits for oxygen. This produces the characteristic sigmoidal (S-shaped) oxygen-hemoglobin dissociation curve. Compare this to myoglobin, which has only one subunit and produces a hyperbolic curve; myoglobin binds oxygen tightly but doesn't release it as readily to tissues.

Oxygen saturation refers to the percentage of hemoglobin binding sites that are occupied by $O_2$ . Pulse oximeters measure this value clinically, and healthy readings are typically 95–100%.

Factors that shift hemoglobin's oxygen affinity

Several factors cause hemoglobin to release oxygen more easily (a right shift of the dissociation curve):

The Bohr effect: When pH drops (more acidic conditions), hemoglobin's affinity for oxygen decreases. Actively metabolizing tissues, like exercising muscles, produce $CO_2$ and lactic acid, lowering local pH. This promotes oxygen unloading right where it's needed most.
2,3-Bisphosphoglycerate (2,3-BPG): This molecule, produced by red blood cells during glycolysis, binds to deoxyhemoglobin and stabilizes its low-affinity state. Higher levels of 2,3-BPG mean more oxygen gets released to tissues.
Temperature: Higher temperatures (again, think exercising muscle) also shift the curve to the right, favoring oxygen release.

Hemoglobin's oxygen binding mechanism, Transport of Gases · Anatomy and Physiology

Carbon Dioxide Transport in Blood

Carbon dioxide is the waste product of cellular respiration, and the blood uses three different methods to carry it from the tissues back to the lungs for exhalation.

Carbon dioxide transport methods

Method	% of Total $CO_2$ Transport	Details
Dissolved in plasma	~7–10%	A small fraction dissolves directly in the blood plasma
Bound to hemoglobin (carbaminohemoglobin)	~20–30%	$CO_2$ binds to the amino groups (not the heme iron) of hemoglobin
As bicarbonate ions ( $HCO_3^-$ )	~60–70%	The dominant transport method, involving enzymatic conversion inside red blood cells

The bicarbonate pathway is the most important and involves a specific sequence of reactions:

$CO_2$ diffuses from tissues into red blood cells.
Inside the red blood cell, the enzyme carbonic anhydrase catalyzes the reaction: $CO_2 + H_2O \rightarrow H_2CO_3$ (carbonic acid).
Carbonic acid quickly dissociates: $H_2CO_3 \rightarrow HCO_3^- + H^+$ .
The $HCO_3^-$ is transported out of the red blood cell into the plasma via an antiporter that swaps it for $Cl^-$ . This exchange is called the chloride shift and maintains electrical neutrality across the red blood cell membrane.
The $H^+$ ions left behind are buffered by binding to hemoglobin, which prevents dangerous drops in blood pH.

At the lungs, this entire process reverses: bicarbonate re-enters the red blood cell, is converted back to $CO_2$ , and the $CO_2$ diffuses into the alveoli to be exhaled.

Hemoglobin's oxygen binding mechanism, 22.4 Gas Exchange – Douglas College Human Anatomy and Physiology I (1st ed.)

Factors Affecting Oxygen-Carrying Capacity

Several conditions can reduce how much oxygen the blood can deliver to tissues, even when the lungs are working normally.

Altitude lowers the partial pressure of oxygen in the air you breathe. At high elevations, hemoglobin can't saturate as fully, which is why people feel short of breath when they first arrive at altitude. Over days to weeks, the body acclimatizes by producing more red blood cells and hemoglobin (stimulated by the hormone erythropoietin). Some populations, like Tibetans, have genetic adaptations that help them thrive at high altitude.

Carbon monoxide (CO) poisoning is especially dangerous because CO binds to hemoglobin's iron with an affinity roughly 200–250 times greater than oxygen. Even small amounts of CO can occupy a large fraction of binding sites, preventing oxygen delivery and causing tissue hypoxia. CO also shifts the dissociation curve to the left, making the remaining bound oxygen harder to release. This is why house fires and poorly ventilated heaters are so hazardous.

Anemia reduces the blood's oxygen-carrying capacity through a lower red blood cell count or decreased hemoglobin concentration. Common causes include:

Iron deficiency, the most common form worldwide, since iron is essential for heme group function. Vegetarian and vegan diets require careful planning to get adequate iron.
Blood loss, such as from heavy menstrual bleeding or injury.
Genetic disorders like sickle cell anemia (abnormally shaped red blood cells that are destroyed prematurely) or thalassemia (reduced hemoglobin production, more prevalent in Mediterranean and Southeast Asian populations).

Methemoglobinemia occurs when the iron in hemoglobin is oxidized from the ferrous state ( $Fe^{2+}$ ) to the ferric state ( $Fe^{3+}$ ). Iron in the $Fe^{3+}$ state cannot bind oxygen. This can be triggered by certain drugs (like benzocaine, a topical anesthetic), chemicals (nitrites), or inherited genetic mutations.

Gas Exchange and Transport Systems

The respiratory and cardiovascular systems work together to ensure continuous gas exchange at two key sites:

At the lungs: $O_2$ diffuses from the alveolar air across the thin alveolar-capillary membrane into the blood, while $CO_2$ diffuses in the opposite direction to be exhaled. This membrane is extremely thin (about 0.5 µm), which keeps diffusion distances short and exchange efficient.
At the tissues: $O_2$ diffuses from the blood into cells to fuel cellular respiration (specifically the electron transport chain in mitochondria), and $CO_2$ , the metabolic waste product, diffuses from cells into the blood.

In both locations, gas movement is driven by partial pressure gradients: gases always diffuse from regions of higher partial pressure to regions of lower partial pressure. The cardiovascular system then acts as the transport link, carrying oxygenated blood from the lungs to the tissues and deoxygenated blood back to the lungs.