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membrane damage

Saturday 4 February 2006

Mechanisms of membrane damage in cell injury

Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species (ROS), which are often produced on reperfusion of ischemic tissues, also cause membrane damage.

Early loss of selective membrane permeability leading ultimately to overt membrane damage is a consistent feature of most forms of cell injury.

Membrane damage may affect the mitochondria, the plasma membrane, and other cellular membranes.

In ischemic cells, membrane defects may be the result of a series of events involving ATP depletion and calcium-modulated activation of phospholipases.

The plasma membrane, however, can also be damaged directly by certain bacterial toxins, viral proteins, lytic complement components, and a variety of physical and chemical agents.

Several biochemical mechanisms may contribute to membrane damage:

- mitochondrial dysfunction

Defective mitochondrial function results in decreased phospholipid synthesis, which affects all cellular membranes, including the mitochondria themselves. At the same time, increase of cytosolic calcium associated with ATP depletion results in increased uptake of Ca2+ into the mitochondria, activating phospholipases and leading to breakdown of phospholipids. The net result is depletion of phospholipids from the mitochondria and other cellular membranes, and accumulation of free fatty acids. In the mitochondria, these changes cause permeability defects, such as the mitochondrial permeability transition, leading to progresive cell injury.

- loss of membrane phospholipids

Severe cell injury is associated with a decrease in the content of membrane phospholipids, because of degradation likely due to activation of endogenous phospholipases by increased levels of cytosolic calcium. Phospholipid loss can also occur secondary to decreased ATP-dependent reacylation or diminished de novo synthesis of phospholipids.

- cytoskeletal anomalies

Cytoskeletal filaments serve as anchors connecting the plasma membrane to the cell interior. Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton.

In the presence of cell swelling, this damage results, particularly in myocardial cells, in detachment of the cell membrane from the cytoskeleton, rendering it susceptible to stretching and rupture.

- reactive oxygen species (ROS)

Partially reduced oxygen free radicals cause injury to cell membranes and other cell constituents.

- lipid breakdown products

These include unesterified free fatty acids, acyl carnitine, and lysophospholipids, catabolic products that are known to accumulate in injured cells as a result of phospholipid degradation. They have a detergent effect on membranes. They also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, potentially causing changes in permeability and electrophysiologic alterations.


- cytoplasmic membrane damage

Plasma membrane damage results in loss of osmotic balance and influx of fluids and ions, as well as loss of proteins, enzymes, coenzymes, and ribonucleic acids. The cells may also leak metabolites, which are vital for the reconstitution of ATP, thus further depleting net intracellular high-energy phosphates.

Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of these enzymes. Lysosomes contain RNases, DNases, proteases, phosphatases, glucosidases, and cathepsins.

Activation of these enzymes leads to enzymatic digestion of cell components, resulting in loss of ribonucleoprotein, deoxyribonucleoprotein, and glycogen, and the cells die by necrosis.

- Damage to mitochondrial membrane