Section 7 Cell Death – Planned and Unplanned

Cell death is a normal and essential part of life.  However, not all cell death is the same.  There are two fundamentally different types:  planned cell death (apoptosis) and unplanned cell death (necrosis).  Understanding the difference between them – and the conditions that trigger each – is central to understanding how disease affects the body.    

Apoptosis:  Planned Cell Death

Apoptosis (sometimes called programmed cell death) is a tightly regulated, orderly process in which aging or damaged cells are eliminated to make room for new, more functional ones.  It is driven by an internal enzymatic cascade involving proteins called caspases, and it results in a clean, contained death that does not trigger inflammation.

Apoptosis in Normal Life

Apoptosis is not a sign of disease – it is a routine, continuous process that keeps tissues healthy.  Consider the following examples:

• Red blood cell (RBC) turnover:  RBCs live approximately 120 days.  Millions undergo apoptosis every day and are simultaneously replaced by new cells produced in the bone marrow.  This balance keeps the RBC population stable.
• Skin cell turnover: Skin cells replace themselves approximately every 30 days through a cycle of apoptosis and mitosis.  Similarly, the epithelial cells lining the mucosa membranes of the respiratory and digestive tracts experience frequent turnover (every 30-50 days and every 3-5 days respectively).
• Embryonic development: Apoptosis plays a critical role in shaping the body before birth.  For example, the webbing between fingers and toes during fetal development is removed through apoptosis, sculpting the final form of the hands and feet.  Heart development and the remodeling of other organs during fetal stages also rely on apoptosis.
• Breast tissue remodeling: During pregnancy, breast tissue grows to support lactation.  After breastfeeding ends, apoptosis returns breast tissue to its pre-pregnancy size.

Note that some cell types – particularly neurons – do not undergo ongoing turnover.  After birth, the number of neurons a person has is largely fixed for life, which is one reason that neurological damage can be so significant.

Triggers of Apoptosis

While apoptosis is normal, it can also be triggered by a variety of stressors.  Triggers are classified as either extrinsic (coming from outside the cells) or intrinsic (arising from within the cell):

The Apoptotic Process:  What it Looks Like

Under a microscope, apoptosis follows a recognizable sequence of steps:

• Step 1 – Cell shrinkage:  The cell shrinks and rounds up.
• Step 2 – Chromatin condensation: The DNA condenses and forms compact patches against the inner surface of the nuclear envelope.
• Step 3 – Nuclear disintegration: The nuclear envelope breaks down and the DNA fragments.
• Step 4 – Membrane blebbing and apoptotic body formation: The cell membrane bubbles outward forming small, membrane bound vesicles called apoptotic bodies.  Each apoptotic body carries transmembrane ‘flag’ proteins that signal macrophages to engulf and recycle it.

The process is clean and efficient.  Macrophages rapidly phagocytose the apoptotic bodies, recycling their components without triggering an inflammatory response – a key distinction from unplanned cell death.

Unplanned Cell Death:  Necrosis

Necrosis occurs when cells are damaged so severely that they burst and die in an uncontrolled manner.  Unlike apoptosis, necrotic cell death is messy – cells lyse (rupture), spilling their contents into the surrounding tissue.  This triggers inflammation: white blood cells, such as neutrophils are recruited to the area and, while they help clean up the debris, they can also cause collateral damage to neighbouring cells through the release of Reactive Oxygen Species (ROS).

The Number One Cause of Unplanned Cell Death:  Ischemia

Ischemia – the interruption of blood flow to a tissue – is the leading cause of unplanned cell death in humans.  When blood flow is blocked or reduced (e.g., by a blocked or compressed blood vessel), three harmful conditions arise simultaneously:

• Oxygen deprivation (hypoxia): Hypoxia (hypo- = below, -oxia = oxygen) means reduced oxygen in tissues.  Without oxygen, cells cannot perform aerobic cellular respiration and ATP production falls dramatically.
• Nutrient deprivation: Glucose, vitamins, and other building blocks essential for cellular function are no longer delivered.  
• Waste accumulation:  Metabolic waste products build up and become toxic to cells.

Together, these three factors cause far more cell injury than oxygen deprivation alone.

How Ischemia Damages Cells:  A Step-by-Step Breakdown

The cellular consequences of ischemia follow a predictable, escalating cascade:

• Low ATP → pump failure: Cells maintain their internal environment using two critical ion pumps that both require ATP:  the sodium-potassium pump (which moves 3 Na⁺ out and 2 K⁺ in) and a calcium-sodium exchanger (which expels Ca²⁺).  Without sufficient ATP, both pumps fail.
• Calcium accumulation: Ca²⁺ floods into the cell and inappropriately activates two destructive enzymes:
  • Phospholipase: degrades the phospholipids of the cell membrane, cause the cell to lose membrane integrity and become leaky.
  • Protease:  degrades cytoskeletal proteins (the cell’s internal scaffolding), causing the cell to lose its supportive structure and shape.
• Membrane phospholipid depletion:  A third enzyme – phospholipid reacylation synthase – normally replaces phospholipids in the membrane during natural turnover.  This enzyme requires ATP and therefore also fails during ischemia, meaning damaged phospholipids cannot be replenished.
• Sodium and water influx: As the membrane becomes leaky, sodium and water rush into the cell.  The cell swells and may ultimately burst.
• Anerobic metabolism and intracellular acidosis:  in an attempt to survive, the cell has switched to anaerobic cellular respiration (glycolysis alone).  The generates some ATP but also produces large amounts of lactic acid, lowering intracellular pH.  Enzyme function declines as the cell becomes increasingly acidic.

Reactive Oxygen Species (ROS) and Oxidative Stress

Reactive Oxygen Species (ROS) are unstable, highly reactive molecules characterized by an unpaired electron.  Examples include superoxide, hydrogen peroxide, and hydroxide ions.  Although ROS are produced normally by mitochondria as part of metabolic signaling (including regulation of vascular tone – the balance between vasoconstriction and vasodilation), they are kept in check by the cell’s own neutralizing antioxidants.  

Problems arise when ROS production exceeds the cell’s capacity to neutralize them – a state called oxidative stress.  In this scenario, ROS cause damage to cell membranes, proteins, and DNA, promoting inflammation and contributing to cell death.

Causes of Cell Damage and Death:  A Summary

A variety of agents can damage or kill cells:

• Physical damage:  Wounds, cuts, extreme heat (e.g., burns, electrical burns), and extreme cold (e.g., frostbite).  Electric shocks cause burns due to heat from electrical resistance.  High temperatures over 40°C induce vascular injury, disruption of cell membrane and cause blood and protein coagulation leading to cell death and downstream ischemia.  During frostbite, blood vessels in exposed skin vasoconstrict to protect internal organs, depriving skin tissue of oxygen and nutrients and leading to necrosis of the affected tissue.
• Radiation:  Ionizing radiation (X-rays, gamma rays) cause DNA damage, ROS production and cell death.
• Mechanical damage: Tearing or crushing of tissue
• Chemical toxins:  Exogenous toxins (e.g., acids, mercury, lead) or endogenous toxic accumulations (e.g., lipids, abnormal proteins) as discussed above.
• Reperfusion injury:  Restoration of blood flow to ischemic tissue causing intracellular calcium flooding, loss of cell membrane integrity, cell lysis, and ROS-mediated damage.
• Microorganisms:  Bacteria, viruses, fungi (e.g., yeast), helminths, and protozoa cause cellular damage through direct infection and/or inflammatory responses
• Abnormal metabolic diseases: Rare conditions in which toxic waste products accumulate inside cells (e.g., inherited Tay Sachs Disease)
• Malnutrition:  Cells deprived of essential building blocks cannot maintain normal function and may deteriorate and die.
• Fluid and electrolyte imbalance:  Disruptions in the balance of water and electrolytes can be severely damaging to the heart, brain, and kidneys.