Defects​ ​In​ ​Membrane​ ​Permeability 

Some​ ​abnormalities​ ​characterize​ ​cell​ ​injury​ ​regardless​ ​of​ ​the​ ​cause,​ ​and​ ​are​ ​thus​ ​seen​ ​in​ ​a
variety​ ​of​ ​pathologic​ ​situations,​ ​one​ ​of​ ​these​ ​changes​ ​is​ ​described​ ​next. 

Defects​ ​in​ ​membrane​ ​permeability:

Increased​​ ​membrane​ ​permeability​ ​leading​ ​ultimately​ ​to​ ​overt
membrane​ ​damage,​ ​this​ ​is​ ​a​ ​feature​ ​of​ ​all​ ​forms​ ​of​ ​cell​ ​injury
that​ ​culminate​ ​in​ ​necrosis.
*Apoptosis​ ​produces​ ​cell​ ​fragments,​ ​while​ ​the​ ​membrane
remains​ ​intact-​ ​no​ ​leakage​ ​of​ ​organelles​ ​occurs​ ​hence​ ​no
inflammatory​ ​reaction

We're​ ​focusing​ ​on​ ​3​ ​membranes,​ ​which​ ​if​ ​injured,

​ ​Necrosis​​ ​and​ ​not​ ​Apoptosis​ ​occurs:
1. Plasma​ ​Membrane:
Plasma​ ​membrane​ ​damage​ ​leads​ ​to​ ​loss​ ​of​ ​osmotic​ ​balance​ ​and​ ​influx​ ​of​ ​fluids​ ​and
ions​ ​(swelling),​ ​as​ ​well​ ​as​ ​loss​ ​of​ ​cellular​ ​contents.​ ​The​ ​cells​ ​may​ ​also​ ​leak​ ​metabolites
that​ ​are​ ​vital​ ​for​ ​the​ ​reconstitution
of​ ​ATP,​ ​depleting​ ​energy​ ​stores.
2. ​ ​Mitochondrial​ ​Membrane:
Damage​ ​to​ ​mitochondrial​ ​membranes​ ​results​ ​in​ ​decreased​ ​production​ ​of​ ​ATP,​ ​with
many​ ​deleterious​ ​effects​ ​culminating​ ​in​ ​necrosis.
3. Lysosomal​ ​Membranes:
If​ ​injured,​ ​leakage​ ​of​ ​their​ ​enzymes​ ​into​ ​the​ ​cytoplasm​ ​and​ ​activation​ ​of​ ​the​ ​acid
hydrolases​ ​in​ ​the​ ​acidic​ ​intracellular​ ​pH​ ​of​ ​the​ ​injured​ ​(e.g.,​ ​ischemic)​ ​cell​ ​will​ ​result.
Activation​ ​of​ ​these​ ​enzymes​ ​leads​ ​to​ ​enzymatic​ ​digestion​ ​of​ ​cell​ ​components,​ ​and​ ​the
cells​ ​die​ ​by​ ​necrosis.
Lysosomes​ ​contain​ ​many​ ​degrading​ ​enzymes​ ​like​ ​RNases,​ ​DNases,​ ​and​ ​proteases.

Mechanisms​ ​of​ ​Membrane​ ​damage: 

 
1. Reactive​ ​Oxygen​ ​Species​ ​(ROS): 
ROS​ ​can​ ​lead​ ​to​ ​Lipid​ ​Peroxidation​,​ ​which​ ​refers​ ​to​ ​the​ ​oxidative​ ​degradation​ ​of​ ​lipids.
It​ ​is​ ​the​ ​process​ ​in​ ​which​ ​free​ ​radicals​ ​"steal"​ ​electrons​ ​from​ ​the​ ​lipids​ ​in​ ​cell
membranes,​ ​resulting​ ​in​ ​cell​ ​damage.​ ​This​ ​process​ ​proceeds​ ​by​ ​a​ ​free​ ​radical​ ​chain
reaction​ ​mechanism.
As​ ​discussed​ ​in​ ​the​ ​previous​ ​lecture,​ ​ROS​ ​are​ ​produced​ ​in​ ​insignificant​ ​amounts​ ​as
a​ ​result​ ​of​ ​cellular​ ​respiration,​ ​when​ ​the​ ​amount​ ​of​ ​these​ ​free​ ​radicals​ ​increases
(due​ ​to,​ ​for​ ​e.g,​ ​Mitochondrial​ ​malfunction​ ​or​ ​hypoxia)​ ​disorders​ ​happen.

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2. Decreased​ ​Phospholipids​ ​synthesis:
As​ ​a​ ​consequence​ ​of​ ​defective​ ​Mitochondrial
function​ ​and/or​ ​hypoxia​ ​which​ ​both​ ​cause​ ​ATP
depletion​ ​that​ ​decreases​ ​Phospholipid​ ​synthesis
and​ ​deacylation-reacylation​ ​reactions​ ​which​ ​are
necessary​ ​for​ ​phospholipid​ ​turnover.
This​ ​affects​ ​all​ ​membranes​ ​including​ ​the​ ​membranes​ ​of​ ​the​ ​Mitochondria​ ​themselves.

3. Increased​ ​Phospholipids​ ​breakdown: 

Increased​ ​cytosolic​ ​Ca​+2​ ​activates​ ​Phospholipase​ ​enzymes,
resulting​ ​in​ ​further​ ​membrane​ ​disruption​ ​+​ ​accumulation
of​ ​lipid​ ​breakdown​ ​products:
a. Unesterified​ ​free​ ​fatty​ ​acids
b. acyl​ ​carnitine
c. Lysophospholipids
Which​ ​have​ ​a​ ​detergent​ ​effect​ ​on​ ​membranes​ ​causing
changes​ ​in​ ​permeability​ ​and​ ​electrophysiological
alterations.

4. Cytoskeletal​ ​abnormalities: 
Increased​ ​cytosolic​ ​Ca​+2​ ​activates​ ​-Beside​ ​Phospholipases-​ ​Proteases​ ​that​ ​cause​ ​damage
to​ ​the​ ​elements​ ​of​ ​the​ ​cytoskeleton(protein​ ​filaments).

*Increased​ ​Calcium​ ​levels​ ​also​ ​activate:​ ​endonuclease​ ​and​ ​ATPase

Membranes​ ​might​ ​get​ ​damaged​ ​directly​ ​by
-​ ​Bacterial​ ​Toxins 
-​ ​Viral​ ​Proteins 
-​ ​Lytic​ ​complement​ ​component 

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 -​ ​Physical​ ​and​ ​Chemical​ ​agents

Chemical​ ​injury:
Toxins,​ ​including​ ​environmental​ ​chemicals​ ​and
substances​ ​produced​ ​by​ ​infectious​ ​pathogens,​ ​induce​ ​cell​ ​injury​ ​that​ ​culminates​ ​primarily​ ​in
necrotic​ ​cell​ ​death.
The​ ​wrong​ ​usage​ ​of​ ​Drugs​ ​is​ ​a​ ​big​ ​problem​ ​in​ ​Jordan,​ ​over​ ​usage​ ​of​ ​Antibiotics​ ​is​ ​an
example.

Mechanisms​ ​of​ ​Chemical​ ​injury​,​ ​Different​ ​types​ ​of​ ​toxins​ ​induce​ ​cell​ ​injury​ ​by​ ​two​ ​general
mechanism:
o Direct-acting​ ​toxins​​ ​by​ ​combining​ ​with​ ​critical​ ​molecular​ ​component.​ ​Examples​ ​include: 
▪ Mercuric​ ​chloride​ ​poisoning​ ​(as​ ​may​ ​occur​ ​from​ ​ingestion​ ​of​ ​contaminated​ ​seafood)
binds​ ​to​ ​the​ ​sulfhydryl​ ​groups​ ​of​ ​cell​ ​membrane​ ​proteins​ ​causing​ ​inhibition​ ​of
ATP-dependent​ ​transport​ ​and​ ​increased
membrane​ ​permeability. 
▪ Cyanide​ ​poisons​ ​mitochondrial​​ ​cytochrome
oxidase​ ​and​ ​inhibits​ ​oxidative​ ​phosphorylation,
thus​ ​reducing​ ​ATP​ ​synthesis​ ​which​ ​cause​ ​a
reduction​ ​in​ ​Phospholipids​ ​Synthesis​ ​and
deacylation-reacylation​ ​reactions. 
 
o Latent​ ​toxins:
Many​ ​toxic​ ​chemicals​ ​are​ ​not​ ​intrinsically​ ​active​ ​but​ ​must​ ​first​ ​be​ ​converted​ ​to​ ​reactive
metabolites,​ ​which​ ​then​ ​act​ ​on​ ​target​ ​cells.​ ​Understandably,​ ​such​ ​toxins​ ​typically​ ​affect​ ​the
cells​ ​in​ ​which​ ​they​ ​are​ ​activated,​ ​this​ ​is​ ​usually​ ​accomplished​ ​by​ ​cytochrome​ ​P-450​ ​in​ ​the
smooth​ ​ER​ ​of​ ​the​ ​liver​ ​and​ ​other​ ​organs,​ ​examples​ ​include:
▪ The​ ​conversion​ ​of​ ​carbon​ ​tetrachloride​ ​(CCl​4​)​ ​to​ ​the​ ​toxic
free​ ​radical​ ​carbon-trichloride​ ​(CCl​3​)​ ​-principally​ ​in​ ​the
liver-​ ​causing​ ​Lipid​ ​Peroxidation​ ​+​ ​decrease​ ​export​ ​of
lipids​ ​outside​ ​the​ ​liver​ ​leading​ ​to​ ​Fatty​ ​change​ ​-more
about​ ​this​ ​in​ ​the​ ​next​ ​lecture- 
▪ Acetaminophen​ ​(Paracetamol),​ ​An​ ​overdose​ ​or​ ​regular
doses​ ​that​ ​are​ ​taken​ ​while​ ​drinking​ ​alcohol​ ​do​ ​cause​ ​severe​ ​Liver​ ​damage,​ ​know​ ​that
Most​ ​cases​ ​of​ ​acetaminophen-induced​ ​liver​ ​injury​ ​are​ ​caused​ ​by​ ​an​ ​intentional​ ​or
suicidal​ ​overdose. 

DNA​ ​Damage 
Cells​ ​usually​ ​have​ ​mechanisms​ ​to​ ​repair​ ​DNA​ ​damage,
Damage​ ​to​ ​DNA​ ​is​ ​sensed​ ​by​ ​intracellular​ ​sentinel​ ​proteins,
which​ ​transmit​ ​signals​ ​that​ ​lead​ ​to​ ​the​ ​accumulation​ ​of​ ​p53

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protein.​ ​p53​ ​first​ ​arrests​ ​the​ ​cell​ ​cycle​ ​(at​ ​the​ ​G1​ ​phase)​ ​to​ ​allow​ ​the​ ​DNA​ ​to​ ​be​ ​repaired
before​ ​it​ ​is​ ​replicated.
However,​ ​if​ ​the​ ​damage​ ​is​ ​too​ ​great​ ​to​ ​be​ ​repaired(severe​ ​damage​ ​and​ ​accumulation​ ​of
misfolded​ ​proteins)​ ​successfully,​ ​p53​ ​triggers​ ​apoptosis,​ ​mainly​ ​by​ ​stimulating​ ​BH3-only
sensor​ ​proteins​ ​that​ ​ultimately​ ​activate​ ​Bax​ ​and​ ​Bak,​ ​proapoptotic​ ​members​ ​of​ ​the​ ​Bcl-2
family.
 
DNA​ ​damage​ ​causes​ ​include​:
Exposure​ ​of​ ​cells​ ​to​ ​radiation​ ​or​ ​chemotherapeutic​ ​agents,​ ​intracellular​ ​generation​ ​of
Regenerative​ ​Oxygen​ ​Species​ ​(ROS),​ ​and​ ​acquisition​ ​of​ ​mutations​ ​may​ ​all​ ​induce​ ​DNA
damage,​ ​which​ ​if​ ​severe​ ​may​ ​initiate​ ​a​ ​suicide​ ​program​ ​results​ ​in​ ​cell​ ​death​ ​by​ ​Apoptosis​.

Protein​ ​Misfolding​ ​(ER​ ​stress) 

Reversible
If​ ​unfolded​ ​or​ ​misfolded​ ​proteins​ ​accumulate​ ​in​ ​the
ER,​ ​they​ ​first​ ​induce​ ​a​ ​protective​ ​cellular​ ​response
that​ ​is​ ​called​ ​the​ ​unfolded​ ​protein​ ​response.​ ​This
adaptive​ ​response​ ​activates​ ​signaling​ ​pathways
that​ ​increase​ ​the​ ​production​ ​of​ ​chaperones​ ​and
decrease​ ​protein​ ​translation,​ ​thus​ ​reducing​ ​the
levels​ ​of​ ​misfolded​ ​proteins​ ​in​ ​the​ ​cell.
Irreversible
The​ ​accumulation​ ​of​ ​misfolded​ ​proteins​ ​in​ ​a​ ​cell
can​ ​stress​ ​compensatory​ ​pathways​ ​in​ ​the​ ​ER​ ​and
lead​ ​to​ ​cell​ ​death​ ​by​ ​apoptosis.
Intracellular​ ​accumulation​ ​of​ ​misfolded​ ​proteins
may​ ​be​ ​caused​ ​by​ ​abnormalities​ ​that​ ​increase​ ​the
production​ ​of​ ​misfolded​ ​proteins​ ​or​ ​reduce​ ​the
ability​ ​to​ ​eliminate​ ​them.​ ​Abnormalities​ ​like,​ ​Gene
mutations​ ​that​ ​lead​ ​to​ ​the​ ​production​ ​of​ ​proteins
that​ ​cannot​ ​fold​ ​properly;​ ​aging,​ ​infections
especially​ ​viral,​ ​increased​ ​demand​ ​for​ ​secretory
proteins​ ​such​ ​as​ ​insulin​ ​in​ ​insulin-resistant​ ​states;
and​ ​changes​ ​in​ ​intracellular​ ​pH​ ​and​ ​redox​ ​state,
ischemia​ ​and​ ​hypoxia​ ​also.

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 Figure​ ​from​ ​page​ ​46

Figure​ ​from​ ​page​ ​46

 
Ischemic​ ​and​ ​Hypoxic​ ​injury 
Hypoxia or Oxygen deficiency leads to failure of many energy dependent metabolic
pathways, and ultimately to death of cells by necrosis, remember that Anaerobic
glycolysis produces far less amounts of ATP (2 compared to 30 in Aerobic per glucose
molecule)​ ​leading​ ​to​ ​ATP​ ​depletion.

Ischemia is an advanced level of Hypoxia, as not only oxygen but many other
substances aren't being delivered causing more rapidly damage + further ATP
depletion.

Mechanisms​ ​of​ ​ischemic​ ​adaptation:

● If the ischemic cell doesn't die immediately it activates compensatory mechanisms that
are induced by transcription factors of the hypoxia inducible factor 1 (HIF-1) family.
HIF-1 stimulates the synthesis of several proteins that help the cell to survive in the
face​ ​of​ ​low​ ​oxygen:
o vascular endothelial growth factor (VEGF), stimulates the growth of new vessels and
thus​ ​attempts​ ​to​ ​increase​ ​blood​ ​flow​ ​and​ ​the​ ​supply​ ​of​ ​oxygen.
o Some proteins stimulate the uptake of glucose and glycolysis and dampening
mitochondrial​ ​oxidative​ ​phosphorylation.
● Anaerobic glycolysis can generate ATP in the absence of oxygen using glucose derived
either from the circulation or from the hydrolysis of intracellular glycogen, tissues and
organs with great storage of glycogen (Liver and Striated muscle) do survive longer
than​ ​those​ ​with​ ​low​ ​(Brain).

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Mechanisms​ ​of​ ​ischemic​ ​injury:

Reversible​ ​changes​ ​include:​

irreversible​ ​changes​ ​include:​

● Large​ ​densities​ ​develop​ ​in​ ​the​ ​mitochondria​ ​causing​ ​its​ ​damage.
● Damage​ ​to​ ​Lysosomal​ ​membranes
● Massive​ ​influx​ ​of​ ​Ca⁺²​ ​happens​ ​especially​ ​if​ ​the​ ​ischemic​ ​area​ ​is​ ​reperfused
All​ ​of​ ​which​ ​causes​ ​membrane​ ​damage.

Irreversible​ ​changes​ ​lead​ ​to​ ​Necrosis​ ​most​ ​of​ ​the​ ​times,​ ​apoptosis​ ​by​ ​the​ ​mitochondrial
pathway​ ​is​ ​also​ ​thought​ ​to​ ​contribute.

➢ Dead​ ​cells​ ​of​ ​the​ ​ischemic​ ​tissue​ ​may​ ​become​ ​replaced​ ​by​ ​large​ ​masses​ ​of​ ​myelin​ ​figures
which​ ​are​ ​either​ ​phagocytosed​ ​or​ ​degraded​ ​more​ ​into​ ​fatty​ ​acids​ ​and​ ​may​ ​become
calcified.

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Ischemia-reperfusion​ ​injury:
Restoration​ ​of​ ​blood​ ​flow​ ​to​ ​ischemic​ ​tissues​ ​can​ ​promote​ ​recovery​ ​if​ ​they​ ​are​ ​reversibly
injured,​ ​in​ ​certain​ ​situations,​ ​reperfusion​ ​paradoxically​ ​exacerbates​ ​injury​ ​(more​ ​dead​ ​cells
in​ ​addition​ ​to​ ​the​ ​already​ ​irreversibly​ ​injured​ ​cells).

Ischemia-reperfusion​ ​injury​ ​mechanisms​ ​:

1. Inflammation​ ​that​ ​is​ ​induced​ ​by​ ​ischemic​ ​injury​ ​and​ ​mediated​ ​by​ ​cytokines​ ​may
increase​ ​with​ ​reperfusion​ ​because​ ​it​ ​enhances​ ​the​ ​influx​ ​of​ ​inflammatory​ ​cells
(leukocytes​ ​and​ ​plasma​ ​proteins).​ ​The​ ​products​ ​of​ ​activated​ ​leukocytes​ ​may​ ​cause
additional​ ​tissue​ ​injury.​ ​Applying​ ​Anti-cytokines​ ​might​ ​aid​ ​in​ ​decreasing​ ​unwanted
effects​ ​of​ ​inflammation.
2. ReOxygenation:
*Might​ ​increase​ ​the​ ​generation​ ​of​ ​Nitrogen​ ​species,​ ​and​ ​ROS​ ​in​ ​cells​ ​with​ ​damaged
mitochondria​ ​that​ ​cannot​ ​carry​ ​out​ ​the​ ​complete​ ​reduction​ ​of​ ​oxygen​ ​ ​and​ ​ ​ ​defense
mechanisms​ ​may​ ​be​ ​compromised​ ​by​ ​ischemia​ ​which​ ​worsens​ ​the​ ​situation​ ​.
*In​ ​normal​ ​healthy​ ​cells​ ​the​ ​mitochondria​ ​produces​ ​small​ ​amounts​ ​of​ ​ROS​ ​while​ ​in​ ​cells
with​ ​damaged​ ​mitochondria,​ ​restoration​ ​of​ ​high​ ​amounts​ ​of​ ​oxygen​ ​leads​ ​to​ ​an
increase​ ​in​ ​ROS​ ​species​ ​and​ ​hence​ ​more​ ​damage.
​ ​*Reactive​ ​nitrogen​ ​species​ ​act​ ​together​ ​with​ ​reactive​ ​oxygen​ ​species​ ​(ROS)​ ​to​ ​damage
cells,​ ​causing​ ​nitrosative​ ​stress.​ ​Therefore,​ ​these​ ​two​ ​species​ ​are​ ​often​ ​collectively
referred​ ​to​ ​as​ ​ROS/RNS.​ ​ ​Increased​ ​Ca​+2​ ​influx.
3. Activation​ ​of​ ​the​ ​complement​ ​system:​ ​Some​ ​IgM​ ​antibodies​ ​are​ ​deposited​ ​in​ ​ischemic
tissues​ ​for​ ​unknown​ ​reasons​ ​and​ ​once​ ​the​ ​blood​ ​is​ ​restored​ ​complement​ ​proteins​ ​bind
to​ ​those​ ​antibodies​ ​and​ ​lead​ ​to​ ​their​ ​activation​ ​and​ ​so​ ​more​ ​injury.

Clinical​ ​Correlations 
❖ The​ ​identification​ ​of​ ​factors​ ​that​ ​determine​ ​when​ ​reversible​ ​injury​ ​becomes​ ​irreversible
and​ ​progresses​ ​to​ ​cell​ ​death​ ​would​ ​be​ ​very​ ​useful​ ​so​ ​we​ ​may​ ​be​ ​able​ ​to​ ​identify
strategies​ ​to​ ​prevent​ ​permanent​ ​consequences​ ​of​ ​cell​ ​injury.
❖ Leakage​ ​of​ ​intracellular​ ​proteins​ ​into​ ​blood​ ​through​ ​damaged​ ​membranes​ ​provides​ ​a
means​ ​of​ ​detecting​ ​tissue​ ​damage,​ ​CK​ ​&​ ​troponin​ ​in​ ​MI​ ​and​ ​ALT,​ ​AST​ ​&​ ​ALK​ ​in​ ​the​ ​liver
are​ ​examples​ ​of​ ​leakage​ ​that​ ​helps​ ​detect​ ​injuries.
❖ When​ ​a​ ​patient​ ​who​ ​has​ ​suspected​ ​liver​ ​disease,​ ​we​ ​perform​ ​liver​ ​function​ ​tests​ ​to
assess​ ​the​ ​status​ ​of​ ​hepatocytes​ ​i.e​ ​if​ ​they​ ​are​ ​injured​ ​or​ ​not,​ ​in​ ​necrosis​ ​and​ ​apoptosis
as​ ​mentioned​ ​proteins​ ​leak​ ​hence​ ​their​ ​presence​ ​indicates​ ​cell​ ​injury.
❖ In​ ​MI​ ​patients​ ​ ​other​ ​than​ ​physical​ ​examination​ ​and​ ​history​ ​taking​ ​we​ ​perform​ ​tests​ ​on
serum​ ​blood​ ​for​ ​cardiac​ ​enzymes​ ​,​ ​if​ ​they​ ​are​ ​high​ ​we​ ​would​ ​know​ ​that​ ​cell​ ​injury​ ​of
myocytes​ ​has​ ​occurred.

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❖ The​ ​functional​ ​consequences​ ​of​ ​hypoxia​ ​and​ ​ischemia​ ​depends​ ​on​ ​the​ ​severity​ ​and
duration​ ​of​ ​the​ ​deficit.​ ​For​ ​instance,​ ​the​ ​heart​ ​muscle​ ​ceases​ ​to​ ​contract​ ​within​ ​60
seconds​ ​of​ ​coronary​ ​occlusion.

SUMMARY
▪ Different​ ​initiating​ ​events​ ​cause​ ​cell​ ​injury​ ​and​ ​death​ ​by​ ​diverse​ ​mechanisms.
▪ Hypoxia​ ​and​ ​ischemia​ ​lead​ ​to​ ​ATP​ ​depletion​ ​and​ ​failure​ ​of​ ​many​ ​energy-dependent
functions,​ ​resulting​ ​first​ ​in​ ​reversible​ ​injury​ ​and,​ ​if​ ​not​ ​corrected,​ ​in​ ​necrosis.
▪ In​ ​ischemia-reperfusion​ ​injury,​ ​restoration​ ​of​ ​blood​ ​flow​ ​to​ ​an​ ​ischemic​ ​tissue
exacerbates​ ​damage​ ​by​ ​increasing​ ​production​ ​of​ ​ROS​ ​and​ ​by​ ​inflammation.
▪ Protein​ ​misfolding​ ​depletes​ ​essential​ ​proteins​ ​and,​ ​if​ ​the​ ​misfolded​ ​proteins
accumulate​ ​within​ ​cells,​ ​results​ ​in​ ​apoptosis.
▪ DNA​ ​damage​ ​(e.g.,​ ​by​ ​radiation)​ ​also​ ​can​ ​induce​ ​apoptosis​ ​if​ ​it​ ​is​ ​not​ ​repaired.
▪ Inflammation​ ​is​ ​associated​ ​with​ ​cell​ ​injury​ ​because​ ​of​ ​the​ ​damaging​ ​actions​ ​of​ ​the
products​ ​of​ ​inflammatory​ ​leukocytes.

▪ Ischemia​ ​is​ ​more​ ​rapidly​ ​damaging​ ​than​ ​hypoxia​ ​in​ ​the​ ​absence​ ​of​ ​ischemia.
▪ Ischemia:​ ​delivery​ ​of​ ​substrates​ ​is​ ​also​ ​compromised.
▪ Hypoxia:​ ​anaerobic​ ​glycolysis

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