1.5 - Mechanisms of Cell Injury

Different injuries ultimately change a relatively small number of critical cellular systems.

biochemical mechanisms of cell injury

one insult can activate several mechanisms of injury simultaneously

• ATP depletion

• mitochondrial damage

• influx of calcium

• accumulation of reactive oxygen species

• increased permeability of cellular membranes

• accumulation of damaged DNA and misfolded proteins

ATP depletion

almost every active cellular process requires energy

• major causes —

  • reduced oxygen and nutrients

  • mitochondrial damage

  • toxins (cyanide)

• examples —

  • plasma membrane Na⁺/K⁺ pump failure

    • causes increased intracellular Na⁺ and decreased intracellular K⁺

    • results in increased intracellular H₂O, resulting in swelling

  • compensatory increase in glycolysis

    • cell increases anaerobic glycolysis, resulting in increased lactic acid and decreased intracellular pH

    • low pH causes impaired enzyme activity and increased activity of certain acid hydrolases

  • calcium pump failure

    • ATP required to kep cystolic Ca²⁺ low

    • influx of Ca²⁺ causes activation of damaging enzymes

  • structural disruption of protein synthesis apparatus

    • ribosomes detach from RER, resulting in reduced protein synthesis

mitochondrial damage

mitochondria generates ATP and certain proteins capable of initiating apoptosis

• impact —

  • ATP depletion → inability to perform oxidative phosphorylation

  • ROS production

  • formation of mitochondrial permeability transition pore

  • release of pro-apoptotic proteins

• major causes —

  • oxygen deprivation

  • toxins

  • radiation

influx of calcium

excess calcium activates destructive enzymes and promotes mitochondrial dysfunction and apoptosis

• impact —

  • activation of phospholipases, proteases, endonucleases, ATPases

  • induction of apoptotic pathways via activation of mitochondrial caspases

    • excess calcium increase mitochondrial permeability

• major causes —

  • ischemia and toxins → Ca²⁺ enters from intracellular stores or extracellular fluid through damaged plasma membranes

accumulation of reactive oxygen species (ROS)

ROS are highly reactive oxygen-derived molecules capable of damaging lipids, proteins, and DNA

• chemical species with single unpaired electron that are extremely unstable

  • superoxide, hydrogen peroxide, hydroxyl radical, nitric oxide

• production of ROS —

  • mitochondria during respiration → small amounts of superoxide

    • converted to hydrogen peroxide spontaneously or by superoxide dismutase

    • hydrogen peroxide converted to hydroxyl in presence of metals

  • phagocytic white blood cells → developed in phagosomes via respiratory burst

    • phagosome membrane enzyme generates superoxide, which is converted to hydrogen peroxide

    • hydrogen peroxide converted to hypochlorite (bleach) via myeloperoxidase

• accumulation of ROS —

  • depends on rates of production vs removal

  • production increased by → radiant energy, metabolism of chemicals, inflammation

  • removal mediated by → spontaneous decay, enzymes, antioxidants

    • enzymes include glutathione peroxidase, superoxide dismutase, catalase

    • antioxidants block formation of free radicals and scavenge those already formed (vitamins E, A, C; beta-carotene)

• mechanism of action —

  • lipid peroxidation of membranes → attack double bonds of polyunsaturated lipids to release more unstable peroxides

  • protein damage → cross-linkage causes enhanced degradation and loss of enzymatic activity

  • DNA damage → single-stranded breaks result in cell death, aging, malignant transformation

• free radicals in low concentrations are important for cellular signaling pathways, immune function, and other physiological reactions

defects in membrane permeability

severe membrane damage is a major feature of irreversible injury and necrosis

• mechanisms of damage —

  • decreased phospholipid synthesis with diminished ATP levels

  • increased phospholipid breakdown → increased Ca²⁺ activates phospholipases

  • ROS damage via lipid peroxidation

  • cytoskeletal damage → increased Ca²⁺ activates proteases that degrade cytoskeletal proteins

  • lipid breakdown products → detergent effect on membranes that can disrupt membranes or insert into them and disturb electrophysiology

• important sites of membrane damage —

  • mitochondrial membrane → decreased ATP

  • plasma membrane → loss of osmotic balance

  • lysosomal membrane → leakage of enzymes

    • acid hydrolase activated by acidic pH from compensatory glycolysis forming lactic acid

    • ribonucleases, DNAases, proteases

    • enzymatic digestion of cellular components setting cells on path of irreversible cellular injury

damage to DNA and proteins

• DNA → cells possess DNA repair systems

  • excessive damage triggers apoptosis

• misfolded proteins → resulted from ROS damage or inherited mutations

  • contains potential to trigger apoptosis