The mitochondrial free radical theory of aging Flashcards
who coined the mitochondrial free radical theory
Denham Harman 1956
what does the mitochondrial free radical theory state
lifespan is an inverse function of metabolic rate which in turn is in proportion to oxygen consumption
which molecules can ROSs cause damage to
DNA, RNA and lipids etc
which observations lead to the MFRT
there is a strong correlation between age and level of ROS, mitochondrial function is gradually lost during aging, inhibiting mitochondrial function can enhance ROS production and several age related diseases are associated with oxidative stress
when are radicals formed
when a non radical loses or gains and electron
give 5 examples of ROS
superoxide anion, hydroxyl anion, hydroxyl radical, hydrogen peroxide and peroxide
what are 3 cellular sources of ROS
leukocytes, macrophages and mit electron transport
what are 3 environmental factors which can cause ROS in body
x-rays, toxic chemicals, insecticides
how are ROS a byproduct of ETc
leakage of complexes 1 and 3 leading to partial reduction of oxygen producing superoxide anion
what are the negative effects of ROS on the membrane
can pair oxidise lipids leading to damage of lipoproteins
what are the negative effects of ROS on the DNA
strand breaks and mutations
what are the negative effects of ROS on proteins
aggregation and fragmentation and inhibition of enzyme action
why are sub cellular organelles highly sensitive to oxidative attack
Extraction of hydrogen from unsaturated fatty acids in the organelles leads to a conjugated diene. when oxygen is taken up into the organelle it forms a peroxy-radical. the H atom from the other FA molecule can then cause autocatalytic chain reaction with the conjugated diene leading to peroxidation of many lipid molecules in the cell and membrane
what is the major product of DNA oxidation
8-oxo-dG
which amino acids are most susceptible to oxidation
tyrosine, histidine, cysteine and methionine
what is the result of protein peroxidation
radical formation which can provide more H donors to next molecule of protein or cysteine cross linking
how do antioxidants protect against oxidative stress
donates electron or hydrogen, acting as a scavenger for reactive molecules
how does superoxide dismutase act as an antioxidant
it converts superoxide to hydrogen peroxide
how does catalase work as an antioxidant
converts hydrogen peroxide to water and o2 preventing lipid preoccupation and protein oxidation
how does glutathione oxidase work as an antioxidant
leads to the neutralisation of hydrogen peroxide to water
which enzyme is responsible for neutralising superoxide anion between complex 1 and 2 of the ETC
manganese superoxide diastase follow by catalase and glutathione oxidase
where is copper/zincSOD found
in inter membrane space
how does vit E act as an antioxidant
prevents oxidation of lipids by donating electrons
how does vitamin c act as an antioxidant
it neutralises several radical species
how does vitamin A act as an antioxidant
carotenoids prevent lipid oxidation
summarise some of the evidence for MFRT
in drosophila hydrogen peroxide production from mit. increases with age, ROS production is much lower in long lived drosophila, old animals show an increase in oxo-8-dG, mice lacking SOD show shortened lifespan and SOD2 KO mice (which codes for SOD) leads to neonatal lethality and overexpression of genes encoding catalase and SOD is sufficient for lifespan extension in drosophila (but not mice)
what evidence is there to contradict the MFRT
there is a lack of correlation between level of ROS nd longevity, administration of antioxidants can be deleterious, in some cases inactivation/overexpression of antioxidant species fails to produce expected results, there exist mutants and long-lived species with high levels of ROS, SOD KO c.elegans mutants live as long as WT with normal levels of mutations, the naked mole rat is the longest lived rodent but has highest levels of ROS
describe the role of ROS in signal transduction
they are second messengers with specific targets and there signalling effects can be reversible. they are involved in the ERK/JNK/MAPK pathways to maintain cellular homeostasis
what can we conclude about the validity of MFTR
ROS do not cause aging although high levels can contribute to disease state
