outline o 2 discovery o 2 sensing o 2 utilization non-shivering thermogenesis -brown fat
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Outline-O2 discovery-O2 sensing -O2 utilization
Non-shivering Thermogenesis-Brown fat-Amino-acids
Oxygen The capable electron acceptor
Oxygenic Photosynthesis
consists of two photosystems, I and II
4e-
O2 + 4H+
2H2O
Photosystem II performs only when Photosystem I is present to dispose e-
Chlorophyll
NADP/NADPH
e- tp chain
Photosystem I
Light(4 photons)
Chlorophyll Chlorophyll + e-
Photosystem II
ADPATP
e- tp chain
Light(4 photons)
Chlorophyll
+ 1.1 V
An-oxygenic Photosynthesis
Either Photosystem I or Photosystem II
Never both.
Source of electrons :
Molecular Hydrogen
or
Inorganic molecules such as (S2).
An-oxygenic species
Heliobacillus
ChlorobiumH2S
S2
S2
H2S
Type I
Type I
Type I
Type II
Chlorobium
Heliobacillus
Loss of type II
Protocyanobacterium
e-
e-
e-
e-
H2S
S2
S2
H2S
Type I
Type I
Type I
Type II
Chlorobium
Heliobacillus
Loss of type II
Protocyanobacterium
e-
e-
e-
e-
Modified from Allen & Martin, Nature 2004
Protocyanobacterium
An-oxygenic Photosynthesis
Is there anything like Protocyanobacteria today?
Allen & Martin, Nature, 2007
Oscillatoria limnetica, a true cyanobacterium, turns off its genes for Photosystem II in the
presence of H2S and thus reverts from
Oxygenic to An-oxygenic Photosynthesis
Discovery of Oxygen
1674Mayow:Demonstrated that only one part of air was necessary for life. That part was removed both by respiration and by fire ”Nitro ariel spirits” (NAS)
NAS
NA
S
NASNASNAS
NAS
NAS
NAS
NAS
NAS
H2O
NAS NAS
NASNAS NAS
The Phlogiston Theory
All combustible materials contain a ”phlogiston” that escape during burning
Discovery of Oxygen
Priestley’s experiment, August, 1774.
2Hg + ”Air” + heat 2HgO
2HgO + intense heat 2Hg+ ”Air”
Reported to the Royal Society, March 1775 and demonstrated that a mouse survived better in ”Air” from heated HgO.Called it both ”Dephlogisticated air” and ”Fire Air”.
Discovery of Oxygen
Scheele, also a Phlogistonist, did the same experiments already 1773.
Sent a letter to Lavoisier in September 1774.
No response; the letter was lost.
Lavoisier denied having seen the letter.
Priestley visited Lavoisier in October, 1774 and discussed his experiment.
Lavoisier repeated and confirmed.
Lavoisier published and called the air ”eminently breathable air”.
He never referred to Priestley or Scheele. Several years later Lavoiser
called this ”air” - Oxygen.
John W SeveringhausActa Anaesth Scand, 2002
Discovery of Oxygen
It was re-discovered by
E. Grimaux in 1890 in a collection of
papers that belonged to MarieAnne Lavoisier.
Grimaux published the text but the original
was lost again.
Re-re-discovered, however, in 1993, when donated
to Archives de l’Académie de Sciences
What about Scheeles letter ?
John W SeveringhausActa Anaesth Scand, 2002
Discovery of Oxygen
Who should goto Stockholm
December 10?
From the hands of ....
...His Majesty The King
Hence,Scheele and Priestley discovered ”Fire Air”
Lavoisier repeated the experiments. Understood the physiological role of ”Fire Air” and later called it Oxygen.
Oxygen Sensing
In all oxygen consuming mammalian cells the transcriptionfactor Hypoxia Inducible Factor, HIF, is a key regulator
The Discovery of HIF opened up for delineation of molecular mechanisms of oxygen regulated gene expression
Gregg Semenza, Cell, 1999
Oxygen Sensing
Cellular Hypoxia stabilizes HIF-1
HIF-1 is capable of activating over 70 genes
In response to hypoxia which
mediates adaptive
physiological responses
such as
Angiogenesis
Erythropoieses
Glycolysis
Gregg Semenza, 2006
Oxygen Sensing
Acute response to hypoxia occurs in seconds or few minutes and involves pre-excisting proteins.
Chronic response to hypoxia occurs in a few minutes or more involves gene expression and synthesis of new proteins
Gregg Semenza, Progress in Biophysics and Molecular Biology, 2006
hyperoxia preferred hypoxiafr
actio
nso
f an
imal
s
20 18 16 14 12 10 8 6 4 2 0
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
% oxygenhyperoxia preferred hypoxia
frac
tions
of a
nim
als
20 18 16 14 12 10 8 6 4 2 0
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
% oxygen
Oxygen Sensing
Bargmann, 2006
Genes encode for various soluable Guanylyl Cyclases (sGC) which bind oxygen
Oxygen 0% 21% Oxygen
1 2 3 4 5 6 7 8 9
bins Oxygen 0% 21% Oxygen
1 2 3 4 5 6 7 8 91 2 3 4 5 6 7 8 9
bins
lessons from a 1mm worm and sGC
These locomotion patterns varies with the sGC’s.Hence, sGC is an important oxygen sensor
Oxygen SensingH
IF-1
pro
lyl h
ydro
xyla
tion Normoxia
HIF-1
Fe2+
-ketogluterate
Prolylhydoxylases
HIF-1VHL-protein
UbiguitinationProteosomedegrading
HIF-1inactivated
Hypoxia
HIF-1Prolyl
hydoxylasesinhibited
HIF-1no binding to VHL-protein
HIF-1 stabilized and activates
genes
Oxygen Utilization
Two Aspects Non-Shivering Thermogenesis
1. The Brown Adipose Tissue, BAT
2. Amino Acids, AA, as fuels for heat production
Oxygen Utilization
Neonatal patho-physiology
Organ development - immaturity
Temperature balance-BAT
Oxygen Utilization
birth
Nor
epin
ephr
ine
(nm
ol/l)
parturitionafter birth
Lagercrantz et al 1994
100 80 60 40 30 20 10
5
2
1
0.5
0.2
Oxygen Utilization
3 6 9 cmcervixdilatation
1/2 2 24 h20 25 30 35 w gestational age
Norepinephrine during normal delivery
Isolated brown fat cells respondto norepinephrine with increased
O2 consumption: thermogenesis
Oxygen Utilization
ACß3 cAMP
PK
acyl-CoA FFA
acyl-carn
acyl-CoA ß-oxidation CAC
ATP
respiratorychain
proton circuit
H+
cell membrane
NE
HSL
thermogenin
mitochondrial membrane
ß3
lipiddroplet
Oxygen Utilization
NENE
oxygen electrode
oxygen electrode
Oxygen Utilization
400
0
NE
2 min
O
Control cells
min . cell400
0
NE
2 min
fmol O
Control cells
min cell
Oxygen Utilization
Control
+3% halothane
Oxygen Utilization
Halothane and other volatile anesthetic
agents inhibit oxygen utilization in BAT,
reduce heat production and hence
thermogenesis.
This leads to thermoregulatory problems
in newborns during surgery
Oxygen Utilization
Where is the effect located ?
Oxygen Utilization
ACß3
cAMP
PK
acyl-CoA FFA
acyl-carn
acyl-CoA ß-oxidation CAC
ATP
respiratorychain
proton circuit
H+
cell membrane
NE
HSL
thermogenin
mitochondrial membrane
ß3
lipiddroplet
Oxygen Utilization
Cold-acclimated hamster as a modelfor the newborn child
Oxygen Utilization
Cold-acclimated hamster as a modelfor the newborn child
Oxygen Utilization
Oxygen Utilization
10 53 12 49
NE NE
ml O2
kg0.75 • min
Oxygen consumption in awake hamster
10 min
910510Female hamster28 w old, cold-adapted 10 wbw. 0.220 kg
1% O2
10 53 12 49
NE NE
ml O2
kg0.75 • min
Oxygen consumption in awake hamster
10 min
910510Female hamster28 w old, cold-adapted 10 wbw. 0.220 kg
1% O2
RMR-1 RMR-2 RMR-3 NE-2 NE-1
NENE-2
-1
0
% O2
B. Halothane
3% 1.5% halothane
10 min
Oxygen Utilization
Hibernation in Medicine
Anti-arrhythmics?
Organ protection?
Oxygen Utilization
Where is the defibrillator?
Hibernation in Medicine
Anti-arrhythmics
Oxygen Utilization
Neonates almost never develop ventricular fibrillation just like hedge-hogs, ground squirrels and other hibernators
Hibernation in Medicine
Anti-arrhythmics
Several explanatory mechanisms such as different:
• pattern of adrenergic innervation
• melting points for lipids
• enzyme temperature activity curves
• handling of intracellular Ca2+
• increased size and nos. of connexin-43 gap junctions
Oxygen Utilization
O2 dependent
oxidative phosphorylation produces ATPthat is consumed within seconds
When O2 drops, oxidative phosphorylation
becomes less efficient and free radicals are produced
Protection from this is a clinical target
with implications on surgical procedures,
trauma, organ preservation/transplantation
Oxygen Utilization Hibernation in Medicine
Organ protection
SCIENCE, 2005
H2S Induces a Suspended Animation-like State In Mice
Eric Blackstone, 1,2 Mike Morrison, 2 Mark B. Roth2*
Oxygen Utilization
80 ppm H2S for six hours
CO2 production and O2 consumption dropped
Oxygen UtilizationHibernation in Medicine
Organ protection
120
100
80
60
40
20
0- 5 minutes + 5 minutes - 6 hours + 1 hour discovery
Carbon Dioxide Production Oxygen Consumption
%
120
100
80
60
40
20
0- 5 minutes + 5 minutes - 6 hours + 1 hour discovery
Carbon Dioxide Production Oxygen Consumption
%Core body temperature decreased to 12oC
Recovery after six hours
Follow-up normal
Hibernation in MedicineOrgan protection
Roth and Nystul ”showed that hibernation states can be induced on demand on animals that do not
naturally hibernate” – using H2S!!
Oxygen Utilization
Scientific American June 2005
H2S reduces oxidative phosphorylation due to a specific,
potent and reversible binding to complex IV (cytocrome c oxidase) preventing oxygen from binding
Oxygen UtilizationHibernation in Medicine
Organ protection
Beauchamp Jr 1984
H2S blocks cells from using O2 and
triggers suspended animation in mice
Oxygen UtilizationHibernation in Medicine
Organ protection
Oxygen UtilizationHibernation in Medicine
Organ protection
Allen & Martin, Nature, 2007
Oscillatoria limnetica, a true cyanobacterium, turns off its genes for Photosystem II in the
presence of H2S and thus reverts from
Oxygenic to An-oxygenic Photosynthesis
An-oxygenic Photosynthesis
Either Photosystem I or Photosystem II
Never both.
Source of electrons :
Molecular Hydrogen
or
Inorganic molecules such as (S2).
An-oxygenic species
Heliobacillus
ChlorobiumH2S
S2
S2
H2S
Type I
Type I
Type I
Type II
Chlorobium
Heliobacillus
Loss of type II
Protocyanobacterium
e-
e-
e-
e-
H2S
S2
S2
H2S
Type I
Type I
Type I
Type II
Chlorobium
Heliobacillus
Loss of type II
Protocyanobacterium
e-
e-
e-
e-
Modified from Allen & Martin, Nature 2004
4e-
O2 + 4H+
2H2O
4e-
O2 + 4H+
2H2O
With regard to ischemia-reperfusion:
The shift into ”suspended animation”, using
H2S, is an interesting mechanism that might
be clinically useful
Oxygen UtilizationHibernation in Medicine
Organ protection
Amino acid-induced thermogenesis
during anesthesia
Oxygen Utilization
Adminstration of oral protein or i.v. amino acids in the awake state is accompanied by approximately 20 % rise in energy expenditure and heat production
AWAKE
Oxygen Utilization
Brundin & Wahren, Metabolism 43, 1994
The thermic effect ofi.v. amino acids is normal or supranormal in the spinal man
TETRAPLEGIA
Oxygen Utilization
Aksnäs et al., Clin Physiol 15, 1995
0
50
100
150
Con
trol
148
0
50
100
150
Con
trol
148
Con
trol
148 Am
ino
acid
s
84
Am
ino
acid
s
84
0
25
50
75C
ontr
ol
47
0
25
50
75C
ontr
ol
47
Con
trol
47
Am
ino
acid
s
26
Am
ino
acid
s
26
21
4
Am
ino
acid
s
4
Am
ino
acid
sA
min
oac
ids
VO2, mL/min
During AnesthesiaDuring Anesthesia AwakeAwake
Watts (J/s)
Oxygen Utilization
Is the heat produced in
- Splanchnic
or
- Extra Splanchnic Tissue ?Oxygen Utilization
70
50
30
10
0
60
40
20
Awakesubjects
Whole body
Splanchnic
Wat
ts
Oxygen Utilization
During anesthesiaand surgery
At awakening Awakesubjects
70
50
30
10
0
60
40
20
Whole body
Splanchnic
Amino acid-induced thermogenesis in whole body and splanchnic region
During anesthesiaand surgery
At awakening Awakesubjects
70
50
30
10
0
60
40
20
Whole body
Splanchnic
Amino acid-induced thermogenesis in whole body and splanchnic region
Oxygen Utilization
What happens in the skeletal muscle cell ?
Is it un-coupling of respiration from ATP synthesis ?
Skeletal muscleUCP 2 and UCP 3 Expression of UCP 2 & 3 mRNAincreased in Tetraplegia
Hjeltnes et al. Diabetologia 1999
Mitochondrial membrane
UCP 1.
Neonates&
Hibernators
BAT
UCP 3 may be a determinant of EEand metabolic efficiency
Schrauwen et al. Diabetes 1999
Oxygen Utilization
Speculations
Release of central inhibition ? Un-coupling in skeletal muscle?
Oxygen Utilization
Normal,awake Spinal, awake Normal, anesthetized
20% >20% 5 fold
CrewAnette EbberydRingvor Hägglöf
Ingeborg Gottlieb-Inacio
Oxygen Consumption – Heat Production
Jan NedergaardBarbara CannonKerstin OlssonEric GrigsbyDonna Meyer
Eva SelldenJohn Wahren
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