ROS

1
ROS

• Reactive oxygen species (eg O2-, OH. ) are one of
  the most important sources of damage (UV,
  glucose,..)Evidence of oxidative damage in many
  diseases.Build up with age and age associated
  with more oxidative environment
• Overview ROS in context
• Production Mitochondria, immune system
• Damage and Repair DNA, proteins, lipids
• Defence - antioxidants
• Interventions supplements, DR, exercise

2
ROS production - I

• Mitochondria ATP generating organellesE.T.C.
  system common to all life
• electron leak - birds, bats, other mammalsState
  3 and 4
• Turtles, ischemia/reperfusion

3
ROS production - II
Immune Response CVD, autoimmune disease
Neutrophils oxidative burst
ROS
T-cells
time
Cell signalling linked to redox state of
cellMany receptors insulin, vegfMany
transcription factors NF-Kb, AP-1
4
ROS damage repair - I

• Cell LD to cause 90 decrease in DNA
  synthesisDNA repair PARP I

5
ROS damage repair - II

• O2-, H2O2, OH. (Fenton reaction Fe2
  Fe3)DNA
• Nuclear e.g. 2/3 of cancers p53 mutation (fast
  turnover rate?)
• Mitochondrial 13 genes for ETC, no histones,
  gene dense, little repair capacity. Depend on
  turnover for repair, doubling and removal by
  lysosomes. Mitotic (clonal expansion) and
  postmitotic (build up of large or metabolically
  inactive)
• Telomeric critical length signals damage,
  checkpoint arrest
• Lipids (phospholipids and glycolipids containing
  FAs)Lipid peroxidation in Membrane, close to
  source of ROS Initiation - abstraction of H. or
  addition of OH. propagation - O2 or RH to form
  ROO(H)
• termination - with another radicalMUFA and PUFA
• LDL and CVDVitamin E

6
ROS damage repair - III
ProteinsProtection by chaperonesTurnover
renewal and degradation by proteosome
7
ROS defence - I

• Enzymatic antioxidantsMnSOD, CuZnSOD, SOD3 02-
  to H2O2 Down syndrome and ADCatalase 2H2O2 -gt
  2H2O O2
• MimeticsGlutathione peroxidase 2GSH H2O2 -gt
  GSSG 2H2O GSH/GSSG ratio key redox
  bufferNon-enzymatic antioxidantsGlutathioneVit
  amin E lipophilic active in membranes
• Vitamin C hydrophilic, acts to renew E. Acts as a
  antioxidant itself but can act as a pro-oxidant
  depending on concentration and the presence of
  iron
• beta-carotene

8
ROS manipulation

• Dietary supplementation Very mixed results
  except in particular cases such as Vitamin E and
  ischemea/reperfusion
• Dietary Restriction (up to 50 LS
  extension) Less evidence of oxidative
  damage Metabolic rate unaltered Mitochondria
  characteristics lipid membrane, less ROS with
  same membrane potential
• Exercise (up to 10 LS extension) Acute can lead
  to immune response and damage Depletion of
  Vitamin E Training generally beneficial with
  more mitochondria produced

9
ROS modelling
Kinetic model of mitochondrial ROS and ATP
generation Kinetics of mitochondria Models of
enzymatic and non enzymatic antioxidant
systems Link to DNA, protein and lipid membrane
damage and repair models