Cell Injury Biochemistry

Overview

Regardless of the type of insult, injury to a cell occurs through a limited set of basic biochemical processes which are discussed in this section. Note that many of these biochemical processes are connected and the precipitation of one pathway can lead to the initiation of others.

Plasma Membrane Damage

The cellular Plasma Membrane is the primary physical structure which allows a cell to maintain an intracellular biochemical environment different from the extracellular space. The Plasma Membrane is maintained in such a way that it provides selective and fine-tuned permeability to many molecules and solutes.

Energy Depletion: The plasma membrane requires constant maintenance through energy-dependent processes, and deficiency of cellular energy stores will eventually lead to breakdown of the barrier
Direct Insult: The plasma membrane can be damaged by direct Chemical Cell Injury or Free Radical Cell Injury which induce physical modification and thus derangement of the molecular components of the membrane

Breakdown of selective membrane permeability is a critical biochemical event that can lead to severe cellular injury. Breakdown can result in the influx of potentially toxic chemicals, release of key cellular nutrients and proteins, as well as elimination of solute gradients across the plasma membrane which are critical for maintaining cellular life. Ultimately, life processes require a physical separation from the environment and elimination of the primary mechanism of biochemical separation will inevitably lead to cellular injury and finally death.

Mitochondrial Damage

Mitochondria are the key organelles of Cellular Respiration and thus provide much of the ATP for energy-dependent cellular processes. Additionally, a variety of potentially toxic molecules are sequestered within the mitochondria, including large stores of calcium as well as key regulators of apoptosis such as Cytochrome C.

A large number of biochemical events can lead to mitochondrial damage and most result in physical damage to the mitochondrial membrane. Commonly, mitochondrial damage is due to increased cytosolic calcium as well as the presence of free radicals, as described below.

Damage to mitochondria results in the elimination of Cellular Respiration and thus precipitous declines in cellular ATP stores. As described below, with insufficient ATP, cells do not possess the requisite energy to maintain a number of key cellular processes. Additionally, damage to Mitochondria can also cause inappropriate release of Cytochrome C, thus inducing pathways of apoptosis which can lead to cell death.

Cytosolic Calcium Derangement

The cytosolic calcium concentration is normally tightly regulated and kept at extremely low concentrations compared to the extracellular environment through ATP-dependent mechanisms. Although small fluctuations in cytosolic calcium are used as a key mediator of intracellular signaling, large increases in calcium concentration can induce activation of potent cellular enzymes which cause severe cellular injury.

Sharp rises in cytosolic concentration can be caused by a variety of biochemical insults. Deficiency of ATP causes slow but steady increases in cytosolic calcium due to an inability to maintain the calcium concentration gradient with the extracellular space. Additionally, damage to the plasma membrane can lead to a loss of selective calcium permeability and result in sharp influxes of extracellular calcium. As mentioned, large amounts of calcium ions are sequestered within the inner mitochondrial matrix and damage to mitochondria can lead to toxic release of these intracellular calcium stores.

Large increases in cytosolic calcium activate a wide variety of potent intracellular enzymes which include proteases, phospholipases, endonucleases, and ATPases. The combined effect of these proteases is wide-spread destruction of intracellular proteins, lipids, nucleic acids, and ATP which together provides a potent insult to cellular survival.

ATP Depletion

ATP is the key currency of cellular energy and is directly required for a wide range of energy-dependent cellular processes. Additionally, for those processes which utilize other energy-rich molecules, ATP is often used as the original energy source used to generate these alternative energetic molecules. Consequently, ATP is either directly or indirectly required for most energy-dependent cellular processes.

The most basic cause of ATP depletion is a lack of oxygen and nutrients which are required Cellular Respiration and glycolysis for generation of ATP. Consequently, Hypoxia or Ischemia are the most common causes of ATP depletion.

Depletion of ATP ultimately causes an end to the wide variety of energy-dependent processes required to maintain cellular life. Possibly the most critical energy-dependent process is maintenance of the plasma membrane, whose interruption results in derangement of membrane permeability as discussed previously.

Nucleic Acid Damage

Nucleic Acids, especially the genome composed of DNA, provide the basic code by which all proteins in the cell are synthesized.

Nucleic Acid damage can be the result Free Radical Cell Injury or due to the activation of nucleases following increases in cytosolic calcium.

Significant damage to the DNA genome generally activates mechanisms of apoptosis which end in programmed cell death.

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