How Cells Change Their Phenotype_10
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Transcript of How Cells Change Their Phenotype_10
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How Cells Change Their
Phenotype
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Damaged protein levels increase.
Protein turnover declines.
DNA damage
Somatic DNA accumulates mutation.
Mitochondrial DNA damage.
Telomere shortening.
Lipofuscin deposits in cells.
Mitochondria function declines. Gene expression changes.
Response to cellular stresses.
Cellular changes
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Changes in senescent cells
Youssef and Badr, 1999
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Mitochondrial DNA lives in a harsherenvironment than nuclear DNA and has muchhigher rates of damage.
mDNA mutation levels rise. mDNA accumulates deletions.
Problem worsened by replication advantage ofmutated mitochondria (muscle especially).
Causes loss of mitochondria function.
Cellular energy production declines.
Mitochondrial DNA damage
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Mitochondrial DNA damage is more extensive and persists
longerthan nuclear DNA damage in human cells following
oxidative stress
A significant amount of reactive oxygen species (ROS) is
generated during mitochondrial oxidative phosphorylation.
Several studies have suggested that mtDNA may accumulate
more oxidative DNA damage relative to nuclear DNA.
A model is presented in which chronic ROS exposure, found in
several degenerative diseases associated with aging, leads to
decreased mitochondrial function, increased mitochondrial-
generated ROS, and persistent mitochondrial DNA damage.Thus persistent mitochondrial DNA damage may serve as a
useful biomarker for ROSassociated diseases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC19544/pdf/pq000514.pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC19544/pdf/pq000514.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC19544/pdf/pq000514.pdf -
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Schematic representation of the role of mitochondria inthe generation of ROS and oxidative stress
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Progressive decrease in the creation ofnew protein.
Reduction in the rate of protein
degradation.
Inaccessible protein deposits.
Result: damaged proteins in cells increase aswe age
Protein turnover
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Muscle mitochondrial protein synthesis
decline
A decline in fractional muscle mitochondrial protein synthesis occurred withage. Approximately a 40 percent decline occurred by middle age (P < 0.01),
but there was no further decline with advancing age. ** Indicates significant
difference from young age. Source: Rooyackers et al., 1996
proteinfr
actionalsynthesis
rate
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An oxidative reaction of glucose with
protein: damages protein and creates
protein-protein crosslinks.
A Maillard reaction of free amino groups
on proteins and glucose.
Advanced Glycosylation End-products:
AGEs
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http://www.chm.bris.ac.uk/webprojects2002/rakotomalala/maillard.htmhttp://www.chm.bris.ac.uk/webprojects2002/rakotomalala/maillard.htm -
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Models of activation of microgliaMicroglia in the normal, healthy brain have a highly branched morphology and a downregulated phenotype. In
response to injury and disease they rapidly change their morphology and upregulate a number of cell-surface
and intracellular antigens such microglia are generally referred to as activated
Nature Reviews Immunology7, 161-167 (February 2007) http://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.html
http://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.htmlhttp://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.htmlhttp://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.html -
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