Primary targets and key pathogenetic pathways
Damaging exogenous or endogenous factors affect key cellular targets: the cytoplasmic membrane, endoplasmic reticulum, and mitochondria.
There are five main pathogenetic pathways in the development of necrosis:
- ATP deficiency due to suppression of oxidative phosphorylation.
- Generation of reactive oxygen species (ROS) and the development of oxidative stress.
- Disruption of calcium homeostasis with cytoplasmic overload by $Ca^{2+}$ ions.
- Protein denaturation upon binding to ubiquitin.
- Loss of selective permeability by cell membranes.
Energy depletion and intracellular acidosis
The drop in high-energy phosphate production in mitochondria leads to the breakdown of ATP residues and an increase in AMP (adenosine monophosphate) concentration. AMP activates anaerobic glycolysis, which entails the rapid utilization and depletion of glycogen reserves.
Enhanced glycolysis leads to the accumulation of lactic acid (lactate). Along with phosphates released during the hydrolysis of ATP and phospholipids, lactate causes intracellular acidosis (decreased pH). Cytoplasmic acidification inhibits most enzymes, yet creates an optimal environment for lysosomal hydrolases, which trigger self-digestion of cellular elements.
Calcium cascade and membrane destruction
The influx of free $Ca^{2+}$ ions from the extracellular space, as well as from the cisterns of the endoplasmic reticulum and mitochondria, activates a group of destructive enzymes:
- ATPases — accelerate the breakdown of remaining ATP reserves, exacerbating energy deficit.
- Phospholipases — break down phospholipids of the cytoplasmic and mitochondrial membranes.
- Proteases — destroy the protein framework of the cytoskeleton.
- Endonucleases (DNase, RNase) — hydrolyze DNA and RNA.
Concurrently, the excessive formation of ROS (singlet oxygen, superoxide anion, hydroxyl radical, hydrogen peroxide $H_2O_2$) causes lipid peroxidation, inhibits cation pumps, and disrupts membrane transport. The loss of selective permeability is also provoked by the action of complement, perforins, lytic viruses, and the formation of hypoxic protein seals during ischemia.
Role of ubiquitin in protein denaturation
Cell injury initiates the synthesis of ubiquitin, a low-molecular-weight protein of 76 amino acid residues inherent to all eukaryotes. In the presence of ATP, ubiquitin forms covalent bonds with lysine bases of proteins, shortening their lifespan through denaturation.
The accumulation of protein-ubiquitin complexes leads to the formation of specific morphological markers:
- Mallory bodies in hepatocytes during toxic alcoholic liver disease.
- Cytoplasmic bodies in CNS neurons during degenerative processes (Alzheimer's disease, Parkinson's disease).
Briefly: answers to topical questions
What morphological changes occur in the nucleus during necrosis (karyolysis, pyknosis, karyorrhexis)?
Morphological changes of the nucleus in necrosis include:
- Pyknosis — shrinking of nuclei accompanied by hyperchromatosis.
- Karyorrhexis — fragmentation of nuclei.
- Karyolysis — dissolution of nuclei and cytoplasm.
In coagulative necrosis, nuclear hyperchromatosis and pyknotic changes appear immediately. In colliquative necrosis, karyolysis, karyorrhexis, and the breakdown of nuclei and cytoplasm join in later. Necrosis is accompanied by chaotic DNA fragmentation.
What are the outcomes of necrosis in clinical practice?
In clinical practice, outcomes of necrosis are divided into favorable and unfavorable.
Favorable outcomes include:
- Organization — replacement of necrotic masses by connective tissue with scar formation.
- Encapsulation — delimitation of the necrotic area by a connective tissue capsule.
- Petrification — dystrophic calcification (deposition of calcium salts).
- Ossification — formation of bone tissue in the area of necrosis.
- Cyst formation — formation of a cavity at the site of a large softening focus.
- Glial scar — replacement of the defect by glial tissue in the brain.
An unfavorable outcome is suppuration — purulent melting of the necrotic zone (septic breakdown).
The acronym A-C-E-M to remember the cascade sequence: Acidosis (lactate accumulation) → Calcium ($Ca^{2+}$ efflux into the cytoplasm) → Enzymes (activation of phospholipases, proteases, nucleases) → Membranolysis (destruction of envelopes and necrosis).
Class and exam questions
Why are calcium ions considered the key mediator of irreversible cell injury?
$Ca^{2+}$ ions activate Ca²⁺-dependent phospholipases, proteases, and endonucleases, which destroy membrane phospholipids, cytoskeletal proteins, and nucleic acids, driving the injury into an irreversible stage.
How does intracellular acidosis affect enzymes in necrosis?
A decrease in pH initiates the suppression of most cytoplasmic enzymes' activity, but simultaneously activates acidic lysosomal hydrolases that cause cellular autolysis.
In which clinical situations does oxidative stress play a leading role?
ROS generation determines the pathogenesis of pneumocyte necrosis in oxygen therapy (neonatal RDS), reperfusion injury in myocardial infarction, and hepatocyte death in paracetamol overdose.
What else to study on this topic
- Specifics of ATP deficiency in ischemic necrosis of cardiomyocytes
- Pathogenesis of reperfusion syndrome upon restoration of blood flow
- Mechanisms of direct membrane-damaging action of viruses and the complement system
- Formation of Mallory bodies in hepatocytes as an indicator of protein denaturation
- Role of lysosomal hydrolases in tissue autolysis
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