Necrosis and apoptosis

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. An example of necrosis is when a blood vessel that feeds an area of the body, say the big toe, becomes blocked and can’t deliver oxygen and nutrients to the cells like usual, it causes ischemia, and the cells die. As a result, the tissues of the toe will turn a nasty shade of black, signaling necrosis.

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 as 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, eventually forming small apoptotic bodies that are eaten by neighboring phagocytes. At the same time, the apoptotic cell releases anti-inflammatory signals, thereby preventing the recruitment of other immune cells from the blood and preventing tissue inflammation. 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.

Alright, let’s switch gears and take a 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. Now, there are three main types of necrosis called primary, secondary, and regulated necrosis.

Primary necrosis, also known as accidental necrosis or oncotic necrosis, typically occurs when ischemia disrupts the normal functioning of mitochondria. As a result, the cell is unable to synthesize ATP, causing all ATP-dependent cellular processes to stop 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 it's followed by water.

This causes the cell to swell up like a balloon. This process of cell swelling is called oncosis. Soon, the cell bursts and spills its internal contents and small molecules called damage-associated molecular patterns into the surroundings.

These molecules trigger the inflammatory response and attract nearby immune cells to release substances like proteases, which are enzymes that degrade proteins, and reactive oxygen species, which are unstable molecules that can 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 primary 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.