Primary Targets and Key Pathogenetic Pathways
Damaging exogenous or endogenous factors affect key cellular targets: the plasma membrane, endoplasmic reticulum, and mitochondria.
Five main pathogenetic pathways of necrosis are distinguished:
- ATP depletion resulting from impaired oxidative phosphorylation.
- Generation of reactive oxygen species (ROS) and development of oxidative stress.
- Disruption of calcium homeostasis with cytoplasmic overload by $Ca^{2+}$ ions.
- Protein denaturation upon their binding to ubiquitin.
- Loss of selective permeability by cell membranes.
Energy Depletion and Intracellular Acidosis
The decline in mitochondrial high-energy phosphate production leads to the breakdown of remaining ATP and an increase in AMP (adenosine monophosphate) concentration. AMP activates anaerobic glycolysis, resulting in the rapid utilization and depletion of glycogen reserves.
- Upregulation of glycolysis leads to the accumulation of lactic acid (lactate). Together with phosphates released during the hydrolysis of ATP and phospholipids, lactate causes intracellular acidosis (decrease in pH). Cytoplasmic acidification suppresses most enzymes while creating 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 endoplasmic reticulum cisternae and mitochondria, activates a group of destructive enzymes:
- ATPases — accelerate the breakdown of remaining ATP stores, worsening energy deficits.
- Phospholipases — degrade phospholipids of the plasma and mitochondrial membranes.
- Proteases — destroy the cytoskeletal protein framework.
- Endonucleases (DNase, RNase) — hydrolyze DNA and RNA.
Simultaneously, excessive ROS formation (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 promoted by the complement system, perforins, lytic viruses, and the formation of hypoxic protein condensates 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 present in all eukaryotes. In the presence of ATP, ubiquitin forms covalent bonds with lysine residues of proteins, shortening their lifespan through denaturation.
Accumulation of protein-ubiquitin complexes leads to the formation of specific morphological markers:
- Mallory bodies in hepatocytes during toxic alcoholic liver injury.
- Cytoplasmic inclusions in CNS neurons during degenerative processes (Alzheimer's disease, Parkinson's disease).