Mechanisms of Cell Injury

Dr Uzma Rihan
MBBS, FCPS, M.Phil Histopathology
Department of Pathology
CMHLMC
 Mechanisms of Cell Injury
 The cellular response to injurious stimuli depends on the
nature of the injury, its duration, and its severity.  

  The consequences of cell injury depend on the type,

nutritional and hormonal status , and adaptability of the injured
cell.

 Cell injury results from different biochemical mechanisms

acting on several essential cellular components
Mechanisms of Cell Injury
 1- DEPLETION OF ATP
 ATP produced by:
 Oxidative phosphorylation of ADP.
 Glycolytic pathway (anaerobic glycolysis)
 Major causes of ATP depletion :
 Reduced supply of oxygen and nutrients
 Mitochondrial damage
 Toxins (e.g., cyanide).
 Tissues with a greater glycolytic capacity (e.g., the liver) are able to
survive loss of oxygen and decreased oxidative phosphorylation better
than are tissues with limited capacity for glycolysis (e.g., the brain).

 Depletion of ATP to 5% to 10% of normal levels has widespread

effects on many critical cellular systems.
 DEPLETION OF ATP

 In cells deprived of oxygen or glucose------> accumulation of

misfolded proteins -----------------> unfolded protein response ------>
Apoptosis.

 Severe & prolonged ATP depletion -----> irreversible damage to

mitochondrial , lysosomal a membranes-------------> leakage of
enzymes----> Necrosis.
 2- MITOCHONDRIAL DAMAGE
• Mitochondria are the cell's suppliers of ATP.
• Mitochondria can be damaged by:
 Increase in cytosolic Ca2+
 Reactive oxygen species (ROS)
 Oxygen deprivation.
 Mutations in mitochondrial genes.

 Three major consequences of mitochondrial damage:

 Decreased ATP
 Production of ROS
 Apoptosis
 2- MITOCHONDRIAL DAMAGE

• Mitochondrial damage/dysfunction
------> failure of oxidative
phosphorylation -----> depletion
of ATP.

• Abnormal oxidative
phosphorylation -----> Reactive
oxygen species
 2- MITOCHONDRIAL DAMAGE

• Increased permeability of the

outer mitochondrial
membrane-------> leakage of
pro-apoptotic proteins
(Cytochrome c) into the
cytosol-----> death by
apoptosis.
 3- INFLUX OF CALCIUM

• Calcium ions are important mediators of cell injury.

• Intracellular calcium (mitochondria and the ER) ---------> 0.1 μmol

• Extracellular levels of calcium---------------------------------> 1.3 mmol.
• Causes of increased cytosolic Ca2+:
 Ischemia
 Certain toxins.
 Injury caused by increased intracellular Ca2+:
 Activation of several enzymes
 Damage to mitochondria ----> decreased ATP production
 Apoptosis by direct activation of Caspases.

  
 4- DEFECTS IN MEMBRANE PERMEABILITY

 Causes of plasma membrane damage (cell membrane,

mitochondria, membranes of lysosomes).
 Hypoxia
 Bacterial toxins
 Viral proteins
 Lytic complement components
 Physical and chemical agents
 Biochemical mechanisms contribute to membrane damage:
 Lipid peroxidation e.g. by ROS
 Decreased phospholipid synthesis e.g. Hypoxia----> reduced ATP
 Increased phospholipid breakdown e.g. intracellular Ca2+ ----->
Phospholipases.
 Cytoskeletal abnormalities by activated proteases by increased
cytosolic calcium ------> detachment of the cell membrane from the
cytoskeleton.
 4- DEFECTS IN MEMBRANE PERMEABILITY

 Consequences of Membrane Damage:

 Mitochondrial membrane damage----------> decreased ATP, and release of

proteins (cytochrom c) that trigger apoptotic death.   

 Plasma membrane damage----------------> loss of osmotic balance and influx of

fluids and ions.

 Injury to Lysosomal membranes --------> leakage of RNases, DNases,

proteases, phosphatases, glucosidases, and cathepsins.
 5- DAMAGE TO DNA AND PROTEINS

• Causes of DNA & Protein damage:

 Drugs
 Radiation
 Oxidative stress or ROS
 Improperly folded proteins by inherited mutations

• Damage to DNA & Accumulation of misfolded proteins-------> Apoptosis

6- ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)
Free radicals are chemical species that have a single
unpaired electron in an outer orbit.
 6- ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)

• Causes of free radicals (ROS) production :

 Chemical and radiation injury
 Ischemia-reperfusion injury
 Cellular aging
• Microbial killing by phagocytes.

• These free radicals react with adjacent molecules,, lipids,

carbohydrates, nucleic acids—many of which are key components
of cell membranes and nuclei.
 6- ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)

 Reactive oxygen species (ROS) are oxygen-derived free radicals.

 ROS are produced normally in cells during mitochondrial respiration and

energy generation.
 Degraded and removed by cellular defense systems.

 ROS are also produced by neutrophils and macrophages in inflammation

 Excessive production of ROS or ineffective- scavenging systems-

Oxidative stress

 Oxidative stress occurs:

 Cell injury by physical, infectious or chemical agents.
 Cancer, aging, and some degenerative diseases such as Alzheimer disease
ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)
 ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)

• Generation of Free Radicals:

 The reduction-oxidation reactions that occur during normal
metabolic processes:
• Superoxide,H2O2 & OH

 Absorption of radiant energy (e.g., ultraviolet light, x-rays).

• Ionizing radiation can hydrolyze water into hydroxyl (OH) and
hydrogen (H) free radicals.

 Enzymatic metabolism of exogenous chemicals or drugs:

• can generate free radicals that are not ROS but have similar effects e.g.,
CCl4 --------> CCl3.
 ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)

• Generation of Free Radicals:

 Transition metals such as iron and copper donate or accept free
electrons during intracellular reactions and catalyze free radical
formation, as in the Fenton reaction :
• H2O2 + Fe2+ ➙ Fe3+ + OH + OH-
 Nitric oxide (NO):
• Generated by endothelial cells, macrophages, neurons, and other cell
types.
• It can act as a free radical and can also be converted to highly reactive
peroxynitrite anion (ONOO-) as well as NO2 and NO3.

 Neutrophils during inflammation produce ROS

 ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)

• Pathological Effects of Free Radicals:

 Oxidation of Lipids in plasma and organelle membranes----->

Disruption of membrane.

 Oxidative Modification of Proteins :

 Loss of enzymatic activity

 Disrupt the structural proteins & accumulation of unfolded or misfolded
proteins.
 ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)

 Oxidative DNA damage --- Cell aging , Mutation & Malignant

transformation
 Single- and double-strand breaks in DNA
 Cross-linking of DNA strands
ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS
Removal of Free Radicals.
The generation, removal, and role of reactive oxygen species (ROS) in cell injury