lecture 10 Flashcards
what is oxidation
gain in oxygen, loss of hydrogen, loss of electrons
what is reduction
loss of oxygen, gain of hydrogen, gain of electrons
what is an oxidant
oxidizes another chemical by taking electrons, hydrogen, or by adding oxygen
what is a reductant
reduces another chemical by supplying electrons, hydrogen, or by removing oxygen
what are free radicals
free radicals attack and snatch energy from other cells to satisfy themselves
what are the most important pro-oxidants
ROS and RNS
what are some examples of free radicals
they have one or more unpaired electrons, so carbon center, nitrogen centered, oxygen centered, and sulfur centered
how are non radicals characterized?
has strong oxidizing potential or help to form strong oxidants
how long can some pro oxidants live for?
- hydrogen peroxide can live for minutes
- nitric oxide can live for seconds
- singlet oxygen can live for microseconds
- hydroxyl radical can live for nanoseconds
what are some endogenous sources of ROS
- endoplasmic reticulum
- cytoplasm
- mitochondria
- lysosomes
- peroxisomes
- plasma membrane
what does 90% of ROS from a cell come from?
the mitochondria, ETC contains several redox centers that may leak e- to oxygen
what is the result of oxidative damage to lipids from mitochondrial oxidative stress?
membrane peroxidation and decreased membrane fluidity
what is the result of oxidative damage to DNA from mitochondrial oxidative stress?
mutations and deletions
what is the result of oxidative damage to proteins as result of mitochondrial oxidative stress
oxidation of sulfhydryl groups, reactions with aldehydes and protein aggregation
where is NADPH oxidase mainly present in?
mainly in neutrophils but still present in many other cell types
why does NADPH oxidase make ROS on purpose?
because absence of ROS will result in chronic granulomatous disease
how does lysosomes generate ROS and RNS
through myeloperoxidase
how does peroxysomes generate ROS and RNS
through enzymes
what does lipid peroxidation lead to?
- structural changes in membranes
- adducts/crosslinkes with non lipids
- direct toxicity of lipid peroxidation products
- dna damage and mutagenesis
what are the structural changes in membranes that come from lipid peroxidation
- alter fluidity and channels
- alter membrane bound signaling proteins
- increases ion permeability
- disruptions in membrane dependent signaling
what are the consequences of protein oxidation?
- oxidation of catalytic sites on enzymes
- formation of mixed sulfide bonds
- increased susceptibility to proteolysis
what are the consequences of DNA oxidation?
- dna adducts/AP sites/strand breaks results in mutations or initiations of cancer
- overstimulation of dna repair
what does oxidation of catalytic sites on enzymes result in?
causes loss of function/abnormal function
what exactly happens in overstimulation of dna repair?
- can deplete energy reserves of cell (PARP)
- induction of error prone polymerases
- activation of checkpoint related signaling pathways
what are the exogenous sources of free radicals?
- irradiation
- chemicals that react to form peroxides
- chemicals that promote superoxide formation
- chemicals that are metabolized to radicals
- iron
what are the ways oxidants can act to modify signal transduction?
- heme oxidation
- oxidation of iron sulfer centers
- changes in thiol/disulfide redox state
- change in conformation
- oxidative modification of proteins
- oxidative modification of dna
- oxidative modification of lipids
what does high does of oxidative stress and cell damage do?
-directly damages and kills cells
what does low doses/chronic overproduction of oxidants do?
- activation of cellular pathways
- stimulation of cell proliferation
- damage to cellular proteins, DNA and lipids
what are defensive mechanisms against pro-oxidants?
- prevention of prooxidant formation
- interception of proxoxidants
- breaking the chain of radical reactions
- repair of damage caused by prooxidants
what is the free radical theory of aging?
steady state accumulation of oxidative damage that increases during aging, progressive loss in efficiency of cellular processes
what are the lessons learned from MnSod knockdown mice?
- mitochondrial antioxidant enzyme peroxide is less dangerous than superoxide
- homozygous mutant is lethal
- 50% decrease in MnSod activity in all tissues studied
- no compensation by other major antioxidant enzymes
what organelle’s function is lost in SOD2 (+/-) mice
mitochondria:
- leads to oxidative damage to specific mito proteins
- altered mitochondrial function leads to decreased activities of ETC
MnSOD hetero knockout mice have same lifespan but have more what?
cancers
what happens when catalase levels decline with age?
hydrogen peroxide cannot be broken down, allows hair to be bleached from the inside out
what is the overall importance of mitochondrial function in aging prevention?
- 3-5 fold increase in point mutations and deletion in mtDNA
- normal appearance until about 6 months, weight loss, kyphosis, decreased fat, osteoporosis
- decreased ETC C activity and ATP production
what kind of dna is more sensitive to oxidative damage than nuclear dna?
mtdna
what chronic diseases are linked to ROS action
- inflammation
- atherosclerosis
- ischemia/reperfusion injury
- injury
tissues that turn over more slowly (skeletal and heart muscle) have more what than more rapidly dividing tissues (liver)?
more mtdna deletion
deletions increase with age in what two organs?
heart muscle and brain
