The mitochondrial free radical theory of aging

Question 1

who coined the mitochondrial free radical theory

Answer 1

Denham Harman 1956

Question 2

what does the mitochondrial free radical theory state

Answer 2

lifespan is an inverse function of metabolic rate which in turn is in proportion to oxygen consumption

Question 3

which molecules can ROSs cause damage to

Answer 3

DNA, RNA and lipids etc

Question 4

which observations lead to the MFRT

Answer 4

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

Question 5

when are radicals formed

Answer 5

when a non radical loses or gains and electron

Question 6

give 5 examples of ROS

Answer 6

superoxide anion, hydroxyl anion, hydroxyl radical, hydrogen peroxide and peroxide

Question 7

what are 3 cellular sources of ROS

Answer 7

leukocytes, macrophages and mit electron transport

Question 8

what are 3 environmental factors which can cause ROS in body

Answer 8

x-rays, toxic chemicals, insecticides

Question 9

how are ROS a byproduct of ETc

Answer 9

leakage of complexes 1 and 3 leading to partial reduction of oxygen producing superoxide anion

Question 10

what are the negative effects of ROS on the membrane

Answer 10

can pair oxidise lipids leading to damage of lipoproteins

Question 11

what are the negative effects of ROS on the DNA

Answer 11

strand breaks and mutations

Question 12

what are the negative effects of ROS on proteins

Answer 12

aggregation and fragmentation and inhibition of enzyme action

Question 13

why are sub cellular organelles highly sensitive to oxidative attack

Answer 13

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

Question 14

what is the major product of DNA oxidation

Answer 14

8-oxo-dG

Question 15

which amino acids are most susceptible to oxidation

Answer 15

tyrosine, histidine, cysteine and methionine

Question 16

what is the result of protein peroxidation

Answer 16

radical formation which can provide more H donors to next molecule of protein or cysteine cross linking

Question 17

how do antioxidants protect against oxidative stress

Answer 17

donates electron or hydrogen, acting as a scavenger for reactive molecules

Question 18

how does superoxide dismutase act as an antioxidant

Answer 18

it converts superoxide to hydrogen peroxide

Question 19

how does catalase work as an antioxidant

Answer 19

converts hydrogen peroxide to water and o2 preventing lipid preoccupation and protein oxidation

Question 20

how does glutathione oxidase work as an antioxidant

Answer 20

leads to the neutralisation of hydrogen peroxide to water

Question 21

which enzyme is responsible for neutralising superoxide anion between complex 1 and 2 of the ETC

Answer 21

manganese superoxide diastase follow by catalase and glutathione oxidase

Question 22

where is copper/zincSOD found

Answer 22

in inter membrane space

Question 23

how does vit E act as an antioxidant

Answer 23

prevents oxidation of lipids by donating electrons

Question 24

how does vitamin c act as an antioxidant

Answer 24

it neutralises several radical species

Question 25

how does vitamin A act as an antioxidant

Answer 25

carotenoids prevent lipid oxidation

Question 26

summarise some of the evidence for MFRT

Answer 26

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)

Question 27

what evidence is there to contradict the MFRT

Answer 27

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

Question 28

describe the role of ROS in signal transduction

Answer 28

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

Question 29

what can we conclude about the validity of MFTR

Answer 29

ROS do not cause aging although high levels can contribute to disease state