4.1 Radiation effects on proteins and lipids

Radiation can wreak havoc on proteins and lipids in our cells. It messes with protein structure and function, leading to enzyme malfunction and wonky cell signaling. Meanwhile, lipids get oxidized, causing membrane chaos and cellular mayhem.

These effects are part of a bigger picture of how radiation damages our cells. From DNA breaks to mitochondrial meltdowns, understanding protein and lipid damage helps us grasp the full impact of radiation on living things.

Radiation Damage to Proteins

Mechanisms of Protein Damage

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• Ionizing radiation causes direct and indirect damage to proteins through free radical and reactive oxygen species (ROS) formation
• Oxidation of amino acid side chains occurs particularly in susceptible residues (cysteine, methionine, tryptophan, tyrosine, phenylalanine)
• Protein crosslinking forms intra- and inter-molecular bonds altering structure and function
  • Examples include disulfide bridges between cysteine residues or carbonyl-amine crosslinks
• Radiation breaks peptide bonds causing protein fragmentation
  • Results in shorter polypeptide chains and loss of functional domains
• Conformational changes in protein structure affect folding and potentially lead to aggregation or denaturation
  • Examples include unfolding of alpha-helices or disruption of beta-sheets

Consequences of Protein Damage

• Loss of enzymatic activity occurs when radiation alters active sites or cofactor binding regions
  • For instance, oxidation of catalytic cysteine in proteases like cathepsins
• Altered cellular signaling results from damaged receptor proteins or signal transduction molecules
  • Example: oxidation of kinase domains in growth factor receptors
• Disruption of protein-protein interactions impacts cellular processes and protein complex formation
  • Radiation damage to binding sites on transcription factors can affect gene regulation
• Accumulation of damaged proteins overwhelms cellular repair mechanisms
  • Leads to proteotoxic stress, potentially triggering apoptosis or cellular senescence
  • Example: buildup of oxidized proteins in the endoplasmic reticulum activates the unfolded protein response

Lipid Peroxidation Mechanisms

Initiation and Propagation

• Lipid peroxidation initiates when ionizing radiation interacts with water molecules generating hydroxyl radicals
• Hydroxyl radicals abstract hydrogen atoms from lipid molecules forming lipid radicals
• Lipid radicals react with molecular oxygen forming lipid peroxyl radicals propagating the chain reaction
• Polyunsaturated fatty acids (PUFAs) show high susceptibility to radiation-induced peroxidation due to multiple double bonds
  • Examples include linoleic acid (18:2) and arachidonic acid (20:4)
• Lipid hydroperoxides form during the propagation phase
  • These unstable compounds decompose to form reactive aldehydes (malondialdehyde, 4-hydroxynonenal)

Biological Implications

• Membrane damage occurs as lipid peroxidation disrupts the lipid bilayer structure
• Increased membrane permeability results from oxidized lipids altering membrane fluidity
• Loss of membrane integrity impacts cellular functions and homeostasis
• Oxidized lipids form adducts with proteins and DNA leading to further cellular damage
  • Example: 4-hydroxynonenal forms covalent bonds with histidine residues in proteins
• Lipid peroxidation products disrupt cellular homeostasis and impair energy metabolism
  • Oxidized cardiolipin in mitochondrial membranes affects electron transport chain efficiency
• Accumulation of lipid peroxidation byproducts triggers inflammatory responses
  • Oxidized phospholipids activate NF-κB signaling pathways promoting inflammation

Antioxidants for Radiation Protection

Enzymatic Antioxidants

• Superoxide dismutase (SOD) converts superoxide radicals to hydrogen peroxide
  • Three forms exist in humans: cytosolic Cu/Zn-SOD, mitochondrial Mn-SOD, and extracellular EC-SOD
• Catalase decomposes hydrogen peroxide into water and oxygen
  • Primarily located in peroxisomes but also found in mitochondria and cytosol
• Glutathione peroxidase reduces hydrogen peroxide and lipid hydroperoxides using glutathione as a cofactor
  • Exists in multiple isoforms with varying tissue distribution and substrate specificity

Non-enzymatic Antioxidants

• Vitamin C (ascorbic acid) directly neutralizes free radicals and regenerates other antioxidants
  • Water-soluble antioxidant found in both intracellular and extracellular fluids
• Vitamin E (tocopherols and tocotrienols) interrupts lipid peroxidation chain reactions in membranes
  • α-tocopherol integrates into cellular membranes protecting lipids from peroxidation
• Glutathione serves as a major cellular antioxidant and cofactor for glutathione peroxidase
  • Exists in reduced (GSH) and oxidized (GSSG) forms maintaining cellular redox balance
• Carotenoids (beta-carotene, lycopene) quench singlet oxygen and neutralize peroxyl radicals
  • Accumulate in cellular membranes providing protection against lipid peroxidation

Antioxidant Mechanisms and Effectiveness

• Free radical scavenging neutralizes reactive oxygen species reducing initial radiation damage
• Metal ion chelation by antioxidants (flavonoids, phytic acid) reduces hydroxyl radical production
• Upregulation of cellular repair mechanisms enhances removal and replacement of damaged biomolecules
  • Nrf2 activation by some antioxidants induces expression of antioxidant and detoxification genes
• Antioxidant effectiveness depends on concentration, localization, and timing of administration
  • Pre-treatment with antioxidants may provide better protection than post-exposure administration
• Combination of different antioxidants often shows synergistic effects in radiation protection
  • Example: vitamin C regenerates vitamin E, enhancing overall antioxidant capacity

Radiation Impact on Membranes

Structural Changes in Membranes

• Lipid peroxidation in cellular membranes alters membrane fluidity and permeability
  • Oxidized lipids increase membrane disorder and create hydrophilic regions
• Radiation-induced oxidation of membrane proteins disrupts their function
  • Affects processes like ion transport, signal transduction, and cell adhesion
  • Example: oxidation of sulfhydryl groups in ion channel proteins alters gating properties
• Changes in membrane lipid composition alter lipid raft structures
  • Impacts cellular signaling and protein trafficking
  • Disruption of lipid rafts affects receptor clustering and signal transduction efficiency

Functional Consequences of Membrane Damage

• Increased calcium influx disrupts intracellular calcium homeostasis
  • Can trigger apoptotic pathways through mitochondrial permeability transition
• Mitochondrial membrane damage impairs energy production and increases oxidative stress
  • Oxidation of cardiolipin affects electron transport chain complexes and ATP synthesis
• Alterations in plasma membrane structure affect cell-cell communication
  • Disruption of gap junctions impacts intercellular signaling and tissue homeostasis
• Extracellular matrix interactions change due to damaged membrane receptors
  • Altered integrin function affects cell adhesion and migration
• Long-term consequences include impaired cellular function and altered cell morphology
  • Chronic membrane damage can lead to genomic instability and potential carcinogenesis
  • Disrupted signaling pathways (MAPK, PI3K/AKT) may promote uncontrolled cell growth