Generally speaking, cells have two ways to die. One way is by apoptosis, which is a form of programmed cell death.

The second way is by necrosis, which is when cells die due to injury or disease.

Overall, apoptosis occurs much more often than necrosis.

One example is when old skin cells undergo apoptosis, and get replaced by new skin cells.

Another example is in our hands and feet during fetal development.

Initially, human hands and feet look like duck’s feet, with webs of skin connecting the fingers.

But the cells in the webbing undergo apoptosis and that allows us to form individual digits that allow us to pick our nose and play the piano.

In contrast, necrosis occurs less frequently, and an example of that is when a blood vessel that goes to your big toe gets clogged causing ischemia, which is where oxygen and nutrients can’t reach the cells.

As a result, those cells begin to die, turning your big toe a nasty shade of black.

In apoptosis, there are two activating mechanisms - the intrinsic pathway, also called the mitochondrial pathway, and the extrinsic pathway, also called the death receptor pathway.

The intrinsic pathway occurs when a cell is exposed to stress like radiation, hypoxia, or low oxygen, a high intracellular concentration of calcium ions, or oxidative stress, which is where reactive molecules with unpaired electrons called free radicals steal electrons from nearby molecules.

These stressors cause two intracellular proteins, Bax and Bak, to move from the cytosol to the mitochondria.

Once in the mitochondria, Bax and Bak pierce the outer mitochondrial membrane making it porous and leaky.

This allows two additional proteins, called SMACS and cytochrome C, to spill into the cytosol.

SMACS binds to proteins that normally inhibit apoptosis and deactivates them.

Meanwhile, cytochrome C binds to both ATP - the main form of intracellular energy - as well an enzyme called Apaf-1.

Together, cytochrome C and Apaf-1 combine to form a large protein complex called an apoptosome.

The Apaf-1 portion of the apoptosome then cleaves an enzyme called pro-caspase 9 into its active form, caspase-9.

Caspase 9 then goes on to activate caspase-3, and caspase-3 goes on to activate other caspases - like a chain event.

Eventually this caspase cascade leads a cell to commit apoptosis.

That’s because these caspases cleave the proteins that make up the cell’s nucleus, organelles, and cytoskeleton - a bit like a ninja sabotaging a bridge by removing its nuts and bolts.

This destroys the cytoskeleton, as well as the proteins that anchor the cytoskeleton to the cell membrane.

As a result, the cell membrane starts to develop blebs - or bulges in the cell membrane.

The blebs are structurally weak, so they start to break off from the cell membrane, and this attracts nearby macrophages, which begin to clean up the mess by eating up the cell fragments.

So apoptosis is a neat process that conveniently recycles the organic contents of the dead cell.

Now, when the signals from apoptosis come from outside the cell - it’s called the extrinsic pathway.

One example is when a nearby macrophage recognizes an old cell, a pathogenic cell, or a cell that has completed its task.

In these situations, a macrophage can initiate apoptosis by releasing tumor necrosis factor alpha or TNF-alpha, a cell signaling protein, that binds to very appropriately named death receptors on the target cell membrane, one example being tumor necrosis factor receptor 1.

The cytosolic end of this receptor, dives deep inside the cell, and it’s called the death domain.

When the TNF-alpha binds to the tumor necrosis factor receptor 1, the death domain changes its shape and is able to bind to two proteins.

One is called Fas-associated protein with death domain or FADD and the other is called take a deep breath here Tumor necrosis factor receptor type 1-associated DEATH domain protein or TRADD.

So the death receptor, FADD, and TRADD come together to form a multi-complex protein called... wait for it... the death-inducing signaling complex or DISC.

Once everything is together, DISC cleaves pro-caspase-8 into caspase-8, which in turn activates caspase-3, and caspase-3 goes on to activate other caspases.

This initiates the caspase cascade that commits the cell to apoptosis.

After that, the process of apoptosis unfolds just like in the intrinsic pathway.

Now in addition to macrophages, if a cytotoxic T cell detects that a cell is expressing foreign antigens, the T cell will express a protein on its membrane called Fas ligand which binds to a death receptor on the target cell called the first apoptosis signal receptor - or Fas receptor.

Similar to the death domain of tumor necrosis factor receptor 1, the Fas receptor protein also has its very own death domain that can bind to FADD to form DISC.

As before, DISC activates pro-caspase-8 into caspase-8 and that triggers the caspase cascade which leads to apoptosis.

Now let’s switch gears and look at necrosis - which can be triggered by external factors like an infection or extremely hot or cold temperatures, as well as internal factors like tissue ischemia.

Necrosis can start one of two ways. The first is a form is called oncosis, which starts when toxins or ischemia damage the mitochondria.

If the mitochondria no longer synthesize ATP, everything stops working - including the ionic pumps that regulate the flow of ions in and out of the cell.

Without functioning ion pumps, sodium starts to flow into the cell and its followed by water which causes the cell to swell up like a balloon.

Soon, the cell bursts and spills its internal contents on neighboring cells, and this attracts nearby immune cells and triggers the inflammatory process.

Immune cells release substances like proteases, which are enzymes that degrades proteins, and reactive oxygen species - which are unstable and damage other cells.

If this inflammatory process occurs among enough cells, it can destroy the tissue, and if it happens on a massive level it can lead to organ dysfunction.

Now it turns out that cell necrosis comes in a few different flavors.

First, there’s coagulative necrosis, which occurs when a tissue becomes hypoxic - has low levels of oxygen - most commonly due to ischemia.

Hypoxia causes structural proteins to bend out of shape - like twisting a paperclip so that it can no longer work.

Hypoxia also affects lysosomal enzymes which become ineffective at getting rid of the affected proteins.

So although the cells die, they retain some structure and don’t get completely destroyed.

From a macroscopic level, the dead tissue becomes a gel-like substance, and has a pale wedge-shape, with the apex oriented towards the obstruction.

That’s because a blood vessel typically serves a region of tissue that typically fans out, and all of that tissue becomes hypoxic and then undergoes coagulative necrosis.

Occasionally, blood re-enters the area of necrosed tissue, like if a blocked blood vessel opens back up - and when that happens it gives the tissue a dark red color and it’s called a red infarct.

Coagulative necrosis can occur in any cell of the body, but it occurs most often when there’s low oxygen to heart, kidney, or spleen tissue.

Next, there’s liquefactive necrosis, and that occurs when hydrolytic enzymes completely digest the dead cells into a creamy substance full of dead immune cells - think of a cream filled donut.

Liquefactive necrosis is most commonly seen in the brain, however, it can also happen to pancreatic cells, or within an abscess located anywhere in the body.

The brain has resident macrophages called microglial cells that contain hydrolytic enzymes.

These enzymes completely destroy damaged brain cells - basically liquefying the dead brain tissue.

Similarly, the pancreas has various enzymes like trypsin that are designed to digest food, but sometimes get activated in chronic inflammation due to gallstones or alcohol consumption, and destroy the pancreatic tissue itself.

Finally, in abscesses, neutrophils use their proteolytic enzymes to liquify tissue - which results in pus.

Next, there’s gangrenous necrosis, and it also occurs due to hypoxia - so, that’s why some consider it a form of coagulative necrosis.

Gangrenous necrosis typically affects the lower limbs and gastrointestinal tract, and it causes the tissue to get dried up like a mummy - sometimes called dry gangrene.

But if the dry gangrene gets infected, then liquefactive necrosis can occur, and then it’s called wet gangrene.

Next, there’s caseous necrosis, and it’s a bit of a mix between coagulative and liquefactive necrosis.

Typically, it’s the result of a fungal or mycobacterial infection - classically Mycobacterium tuberculosis which causes tuberculosis.

The dead cells disintegrate but are not fully digested, which leaves the tissue with a cottage cheese consistency.

Next, there’s fat necrosis, which most commonly occurs when there’s trauma to fatty organs that have a lot of adipose cells, like the pancreas or the breasts.

Trauma to the pancreas or the breasts ruptures the adipose cell membranes, which makes them spill their fatty acids into the extracellular space.

There, the fatty acids combine with calcium, which leads to dystrophic calcifications in the tissue -that look like bits of chalk in the tissue.

Now, in addition, the pancreas can also undergo fat necrosis as a result of inflammation - called pancreatitis.

With pancreatitis, the pancreatic cells spill lipase around the pancreas.

Lipase helps digest fats, so it causes fatty acids to spill out of the fatty retroperitoneal tissue that’s adjacent to the pancreas.

Finally, there’s fibrinoid necrosis which is almost always found in malignant hypertension and vasculitis.

With hypertension, a constant high blood pressure damages the muscular wall of the small arteries, so fibrin - a protein involved in the clotting of blood - starts to infiltrate and damage the walls of the damaged blood vessels.

Similarly, in vasculitis, there’s an inflammatory reaction in the blood vessel walls that causes destruction.