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JOHN ESSIGMANN: We're now on
storyboard 12, session 13.

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00:00:24,930 --> 00:00:26,810
Let's take a look
first at panel A.

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00:00:26,810 --> 00:00:28,370
I mentioned earlier
that respiration

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00:00:28,370 --> 00:00:31,460
is the oxidative metabolism
of all metabolic fuels,

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00:00:31,460 --> 00:00:33,890
carbohydrates as well as lipids.

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If we were starting
with a carbohydrate then

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respiration starts with the
pyruvate dehydrogenase reaction

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00:00:40,250 --> 00:00:42,770
and then proceeds
into the TCA cycle,

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00:00:42,770 --> 00:00:47,330
and then into electron transport
and oxidative phosphorylation.

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00:00:47,330 --> 00:00:50,570
If the acetylcholine comes from
fatty acid oxidation, which

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00:00:50,570 --> 00:00:52,460
we'll cover later,
then we do not

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00:00:52,460 --> 00:00:55,520
have to do the pyruvate
dehydrogenase step.

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00:00:55,520 --> 00:00:58,820
Three molecules of NADH
and one molecule of FADH2

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00:00:58,820 --> 00:01:01,370
are produced as the
carriers of electrons

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00:01:01,370 --> 00:01:03,740
from the intermediates
in the TCA cycle

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00:01:03,740 --> 00:01:08,120
from each input molecule
of acetyl coenzyme A.

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00:01:08,120 --> 00:01:09,740
As I mentioned a
number of times,

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00:01:09,740 --> 00:01:13,970
we look at NADH and FADH2 as
relatively mobile electron

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00:01:13,970 --> 00:01:15,124
carriers.

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00:01:15,124 --> 00:01:16,790
They're going to be
picking up electrons

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00:01:16,790 --> 00:01:19,460
from intermediates and
biochemical pathways

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00:01:19,460 --> 00:01:21,500
and then they bring
those electrons

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00:01:21,500 --> 00:01:23,810
into the mitochondrial
inner membrane, where

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00:01:23,810 --> 00:01:26,900
the reducing equivalents are
passed along to the electron

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00:01:26,900 --> 00:01:28,310
transport chain.

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00:01:28,310 --> 00:01:30,260
Ultimately the
electrons will end up

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00:01:30,260 --> 00:01:34,120
being deposited into
oxygen to make water.

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00:01:34,120 --> 00:01:36,520
Let's turn to panel B
where I'm going to start

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00:01:36,520 --> 00:01:38,440
laying out the big picture.

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00:01:38,440 --> 00:01:40,930
In this small cartoon
we see fuel being

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00:01:40,930 --> 00:01:43,420
oxidized to carbon dioxide.

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00:01:43,420 --> 00:01:46,090
The electrons are passed
to either in NAD-plus,

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00:01:46,090 --> 00:01:49,830
or FAD to form the
reduced cofactor.

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00:01:49,830 --> 00:01:51,910
The reduced co-factors
find their way

42
00:01:51,910 --> 00:01:54,220
to the mitochondrial
inner membrane

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00:01:54,220 --> 00:01:56,110
and the electrons, or
reducing equivalents,

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00:01:56,110 --> 00:01:59,050
are passed to oxygen
to make water.

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00:01:59,050 --> 00:02:01,390
This process is
highly exergonic.

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00:02:01,390 --> 00:02:03,370
And we'll do a model
calculation in a minute

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00:02:03,370 --> 00:02:06,310
to show just how
energy yielding it is,

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00:02:06,310 --> 00:02:09,830
resulting in the liberation
of a lot of free energy.

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00:02:09,830 --> 00:02:13,480
That energy is captured
by the movement of protons

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00:02:13,480 --> 00:02:15,760
from one side of the
mitochondrial inner membrane

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00:02:15,760 --> 00:02:18,310
to the other side
of the membrane.

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00:02:18,310 --> 00:02:21,970
In this process you're taking
a low concentration of protons

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00:02:21,970 --> 00:02:25,540
and creating a relatively
high concentration of protons.

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00:02:25,540 --> 00:02:28,990
That's an uphill process that's
going to require an energy

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00:02:28,990 --> 00:02:31,870
input, and the energy
from nutrient oxidation

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00:02:31,870 --> 00:02:35,650
is what powers this
generation of an ion gradient.

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00:02:35,650 --> 00:02:38,890
Concentrating the protons
in a small defined space

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00:02:38,890 --> 00:02:41,230
is kind of like
charging a battery.

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00:02:41,230 --> 00:02:44,830
It took energy to create that
high concentration of protons.

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00:02:44,830 --> 00:02:48,820
We'll see that nature invented a
way to channel the protons back

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00:02:48,820 --> 00:02:53,110
through a device and a way to
capture the energy released

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when the gradient is dissipated.

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That energy can be
captured in various ways,

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00:02:57,820 --> 00:03:01,860
enabling us to be able to
do useful things with it.

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00:03:01,860 --> 00:03:03,740
For example, the
energy could be used

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00:03:03,740 --> 00:03:06,830
to accomplish the otherwise
energy requiring process

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00:03:06,830 --> 00:03:10,160
of putting a phosphate
onto ADP to make ATP,

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00:03:10,160 --> 00:03:13,970
and that way the energy is
captured in a chemical bond.

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00:03:13,970 --> 00:03:16,280
Alternatively, let's think
of a situation in which

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you may need to generate heat.

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00:03:18,380 --> 00:03:20,060
You could allow
the protons simply

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00:03:20,060 --> 00:03:23,090
to flow back across the
membrane through a channel.

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00:03:23,090 --> 00:03:24,830
The energy of the
proton gradient

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00:03:24,830 --> 00:03:27,170
would then be released as heat.

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00:03:27,170 --> 00:03:30,260
Thirdly, we can perhaps allow
the protons to flow back

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00:03:30,260 --> 00:03:33,530
through a device that
creates rotary movement

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00:03:33,530 --> 00:03:35,780
and that's how, for
example, a flagellar

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motor can spin to move
a bacterium from one

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place to another.

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00:03:40,400 --> 00:03:43,490
Let's now turn to
panel C. We've seen

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00:03:43,490 --> 00:03:45,590
earlier that
oxidation can result

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00:03:45,590 --> 00:03:48,710
in the production
of NADH or FADH2.

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00:03:48,710 --> 00:03:51,590
To begin let's consider NADH.

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00:03:51,590 --> 00:03:54,650
In this panel you can
see the NADH oxidized

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where the electrons
flow-- and it

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00:03:56,210 --> 00:03:57,890
doesn't matter what
the path of the flow

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00:03:57,890 --> 00:04:01,250
is-- all the way to
oxygen. Thermodynamics

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00:04:01,250 --> 00:04:04,210
gives us the tools to
calculate how much energy you

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00:04:04,210 --> 00:04:06,910
would get in this process.

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00:04:06,910 --> 00:04:09,520
JoAnne taught you a lot
about thermodynamics

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00:04:09,520 --> 00:04:11,710
in biological systems,
And this is just

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00:04:11,710 --> 00:04:13,540
a repeat of what she said.

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00:04:13,540 --> 00:04:15,520
But what I'm going
to do is put what

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00:04:15,520 --> 00:04:19,149
she said into a concrete,
practical example.

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00:04:19,149 --> 00:04:21,430
I've drawn out at
the bottom of panel C

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00:04:21,430 --> 00:04:24,640
the overall reaction, showing
electrons going from NADH

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00:04:24,640 --> 00:04:27,940
to oxygen in the
forward direction.

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00:04:27,940 --> 00:04:31,360
Now, of course, we could also
think about the back reaction,

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00:04:31,360 --> 00:04:34,630
where electrons would flow
from water into NAD-plus

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00:04:34,630 --> 00:04:36,400
to form NADH.

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00:04:36,400 --> 00:04:39,110
At this point this is just an
equation on a piece of paper

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00:04:39,110 --> 00:04:40,840
and we don't know
in which direction

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00:04:40,840 --> 00:04:43,240
the reaction is
overall favorable.

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00:04:43,240 --> 00:04:45,850
That is, is it favorable
in the forward direction

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00:04:45,850 --> 00:04:49,120
as drawn, left to right, or
in the reverse direction,

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00:04:49,120 --> 00:04:50,560
right to left?

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00:04:50,560 --> 00:04:52,990
The reaction from left
to right is the direction

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00:04:52,990 --> 00:04:57,130
we usually think about in the
context of nutrient oxidation.

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00:04:57,130 --> 00:05:00,070
Interestingly, the
reaction from right to left

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00:05:00,070 --> 00:05:01,670
is photosynthesis.

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00:05:01,670 --> 00:05:04,060
So both directions
are biologically used,

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00:05:04,060 --> 00:05:06,010
but we'll see that
one of the directions

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00:05:06,010 --> 00:05:09,010
will require substantial
energy input in order

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00:05:09,010 --> 00:05:11,880
to make it biologically useful.

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00:05:11,880 --> 00:05:14,370
Probably you can appreciate
that photosynthesis

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00:05:14,370 --> 00:05:17,130
is the energy requiring
process, because we all

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00:05:17,130 --> 00:05:18,840
know that sunlight
is needed to make

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00:05:18,840 --> 00:05:22,440
the process thermodynamically
and kinetically favorable.

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00:05:22,440 --> 00:05:24,960
We don't cover photosynthesis
in 5.07, so let

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00:05:24,960 --> 00:05:27,080
me say a few words about it.

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In photosynthesis nature
takes electrons from water

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00:05:30,660 --> 00:05:34,110
and uses them to reduce
NADP-plus to NADPH.

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00:05:34,110 --> 00:05:37,560
Note that I said NADP-plus,
and not NAD-plus,

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00:05:37,560 --> 00:05:40,770
but for the purposes
here they are equivalent.

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00:05:40,770 --> 00:05:43,380
In the case of photosynthesis
we know intuitively

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00:05:43,380 --> 00:05:45,810
that the overall process
is powered by light,

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00:05:45,810 --> 00:05:48,630
so in going from right to
left the process intuitively,

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00:05:48,630 --> 00:05:51,390
once again, should
require energy.

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00:05:51,390 --> 00:05:53,760
By contrast, nutrient
oxidation, where

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00:05:53,760 --> 00:05:56,430
we go from left to
right in this equation,

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00:05:56,430 --> 00:05:59,280
should be a process
that generates energy.

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00:05:59,280 --> 00:06:03,220
But intuition aside,
let's do the calculation.

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00:06:03,220 --> 00:06:06,060
So the question is,
in which direction

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00:06:06,060 --> 00:06:09,270
is the equation at the bottom
of panel C thermodynamically

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00:06:09,270 --> 00:06:14,600
favorable-- left to
right or right to left?

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00:06:14,600 --> 00:06:17,380
Let's take a look
now at panel D.

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00:06:17,380 --> 00:06:19,450
You'll see here that I
have split the master

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00:06:19,450 --> 00:06:22,060
equation into half reactions.

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00:06:22,060 --> 00:06:24,340
I always write out
the half reaction

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00:06:24,340 --> 00:06:26,330
in the direction of reduction.

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00:06:26,330 --> 00:06:28,870
For example, look at the
second half reaction.

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00:06:28,870 --> 00:06:31,540
It shows that half
a mole of oxygen

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00:06:31,540 --> 00:06:34,880
plus two protons, plus two
electrons, go to water.

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00:06:34,880 --> 00:06:36,790
Again, I've written
out these reactions

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00:06:36,790 --> 00:06:38,250
in the direction of reduction.

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00:06:38,250 --> 00:06:40,330
It's just the way I do it.

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00:06:40,330 --> 00:06:42,370
Next I go to the
redox chart, that

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00:06:42,370 --> 00:06:45,940
is the table of redox potentials
of electrochemical reactions,

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00:06:45,940 --> 00:06:49,330
and I figure out what the
standard energies are for each

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00:06:49,330 --> 00:06:51,070
of these half reactions.

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00:06:51,070 --> 00:06:56,470
As you can see, it's 0.32
volts, and, plus 0.82 volts

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00:06:56,470 --> 00:06:59,660
respectively, for the
two half reactions.

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00:06:59,660 --> 00:07:02,260
Next I use a variant
of the Nernst equation

154
00:07:02,260 --> 00:07:04,630
to calculate the free
energy and ultimately

155
00:07:04,630 --> 00:07:06,740
the directionality
of the reaction.

156
00:07:06,740 --> 00:07:10,840
The equation I use is
delta G naught prime equals

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00:07:10,840 --> 00:07:13,810
N times Faraday's constant,
times the difference

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00:07:13,810 --> 00:07:16,980
in the reduction potentials
of the two half reactions.

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00:07:16,980 --> 00:07:20,380
To find delta E
naught prime, we look

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00:07:20,380 --> 00:07:22,360
at the reaction that
I've written out,

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00:07:22,360 --> 00:07:24,340
the overall reaction,
and we looked

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00:07:24,340 --> 00:07:27,550
at see which is the
electron acceptor,

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00:07:27,550 --> 00:07:30,040
in which is the
electron donor the way

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00:07:30,040 --> 00:07:32,110
the reaction was written.

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00:07:32,110 --> 00:07:34,480
Then we subtract the
reduction potential

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00:07:34,480 --> 00:07:40,130
of the electron receptor from
that of the electron donor.

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00:07:40,130 --> 00:07:43,070
The way the equation is
written, left to right, oxygen

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00:07:43,070 --> 00:07:44,930
is the electron acceptor.

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00:07:44,930 --> 00:07:49,460
It's reduction potential is plus
0.82 volts, so delta E naught

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00:07:49,460 --> 00:07:55,580
prime is plus 0.8 to
minus a minus 0.32,

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00:07:55,580 --> 00:08:00,870
or a total of plus 1.14 volts.

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00:08:00,870 --> 00:08:02,630
In the Nernst
equation, the number

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00:08:02,630 --> 00:08:04,970
of electrons transferred
in this case is two,

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00:08:04,970 --> 00:08:08,600
and Faraday's constant
is 96.4 kilojoules

175
00:08:08,600 --> 00:08:11,340
per mole times volts.

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00:08:11,340 --> 00:08:13,650
If you do the math,
or as we say at MIT,

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00:08:13,650 --> 00:08:15,960
plug and chug, what
you find out is

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00:08:15,960 --> 00:08:18,950
that the free energy change of
the reaction that's written,

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00:08:18,950 --> 00:08:25,500
the NADH oxidation reaction, is
minus 220 kilojoules per mole.

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00:08:25,500 --> 00:08:29,100
This number is negative and that
means the reaction is favorable

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00:08:29,100 --> 00:08:31,520
as drawn.

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00:08:31,520 --> 00:08:35,090
That is, the reaction
goes from left to right.

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00:08:35,090 --> 00:08:37,940
The 220 kilojoules is
the amount of energy

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00:08:37,940 --> 00:08:40,580
that's available for the
three purposes of the pathway.

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00:08:40,580 --> 00:08:47,140
That is, ATP synthesis, heat
generation, or movement.

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00:08:47,140 --> 00:08:51,910
If we were going to make ATP,
we would divide 220 by 32,

187
00:08:51,910 --> 00:08:54,670
because we get about
32 kilojoules of energy

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00:08:54,670 --> 00:08:57,855
by hydrolysis of ATP,
and we can calculate

189
00:08:57,855 --> 00:08:59,230
that we're going
to get something

190
00:08:59,230 --> 00:09:03,400
in the order of about 3
ATPs for every NADH that

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00:09:03,400 --> 00:09:07,560
gives up two electrons to
the electron transport chain.

192
00:09:07,560 --> 00:09:10,740
We could easily do the same
oxidation reaction and study

193
00:09:10,740 --> 00:09:13,890
FADH2, but in this
case, we would calculate

194
00:09:13,890 --> 00:09:17,280
that we would get actually less
energy, because the oxidation

195
00:09:17,280 --> 00:09:21,330
potential of flavins, as
compared to NAD, is different.

196
00:09:21,330 --> 00:09:24,780
In that case, that
is, FADH2 oxidation,

197
00:09:24,780 --> 00:09:28,950
you would get only about
two ATPs per FADH2 oxidized.

198
00:09:28,950 --> 00:09:32,960
So the FADH2 produced in
the succinate dehydrogenase

199
00:09:32,960 --> 00:09:35,550
step of the TCA
cycle is less energy

200
00:09:35,550 --> 00:09:38,760
yielding than, for example,
the oxidation of malate

201
00:09:38,760 --> 00:09:43,850
to oxaloacetate that occurs
later in the pathway.

202
00:09:43,850 --> 00:09:46,150
Let's turn now to storyboard 13.

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00:09:46,150 --> 00:09:49,100
We now have an idea of
the rough amount of energy

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00:09:49,100 --> 00:09:52,870
that's going to be generated
by nutrient oxidation.

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00:09:52,870 --> 00:09:54,910
Next we're going to
look a little bit more

206
00:09:54,910 --> 00:09:57,700
in detail at the mechanism
by which the electrons are

207
00:09:57,700 --> 00:10:00,550
transported from the
reduced substances

208
00:10:00,550 --> 00:10:04,840
that constitute our electron
donors, NADH and FADH2,

209
00:10:04,840 --> 00:10:08,830
to molecular oxygen, or
whatever the terminal electron

210
00:10:08,830 --> 00:10:12,920
acceptor is in the biological
system under study.

211
00:10:12,920 --> 00:10:15,380
As was seen, the
electron transfer

212
00:10:15,380 --> 00:10:18,620
process that we've been
studying liberates energy,

213
00:10:18,620 --> 00:10:21,290
and that energy is going to
be used to power pumps that

214
00:10:21,290 --> 00:10:25,520
will transport protons from
the matrix of the mitochondrian

215
00:10:25,520 --> 00:10:29,300
out into the intermembrane space
between the mitochondrial inner

216
00:10:29,300 --> 00:10:31,400
and outer membranes.

217
00:10:31,400 --> 00:10:32,870
In the case of
electron transport

218
00:10:32,870 --> 00:10:35,660
with the goal of ATP
synthesis, the protons

219
00:10:35,660 --> 00:10:38,360
that are generated in
the intermembrane space

220
00:10:38,360 --> 00:10:40,640
will be allowed to flow
back through a device

221
00:10:40,640 --> 00:10:42,620
that mechanically
couples motion--

222
00:10:42,620 --> 00:10:44,600
that is the spinning
of a shaft--

223
00:10:44,600 --> 00:10:47,660
to drive conformational
changes in enzymes

224
00:10:47,660 --> 00:10:51,500
that will allow the otherwise
endergonic synthesis of ATP

225
00:10:51,500 --> 00:10:54,800
from ADP in inorganic phosphate.

226
00:10:54,800 --> 00:10:58,900
That machine is called
the ATP synthase.

227
00:10:58,900 --> 00:11:00,970
Let's look at
panel A. This panel

228
00:11:00,970 --> 00:11:04,150
shows the details of the
electron transport system.

229
00:11:04,150 --> 00:11:05,809
It looks a little
bit complicated,

230
00:11:05,809 --> 00:11:08,350
but let's not lose sight of the
fact that what it's all about

231
00:11:08,350 --> 00:11:12,280
is powering pumps,
pumps that pump protons.

232
00:11:12,280 --> 00:11:14,020
In the lower left
of the panel we

233
00:11:14,020 --> 00:11:18,340
see the TCA cycle
generating NADH and FADH2.

234
00:11:18,340 --> 00:11:22,270
The NADH approaches complex
one of the mitochondrial inner

235
00:11:22,270 --> 00:11:24,270
membrane.

236
00:11:24,270 --> 00:11:29,310
Complex one is in an NADH
dehydrogenase enzyme.

237
00:11:29,310 --> 00:11:31,980
The enzyme has a flavin
that accepts the electrons

238
00:11:31,980 --> 00:11:36,090
from NADH, passes them along
to iron sulfur centers,

239
00:11:36,090 --> 00:11:38,064
and then to a variety
of cytochromes.

240
00:11:38,064 --> 00:11:40,230
It moves the electrons up
to the point where they're

241
00:11:40,230 --> 00:11:42,000
going to be
transferred to coenzyme

242
00:11:42,000 --> 00:11:45,270
Q. In its oxidized
form, coenzyme Q

243
00:11:45,270 --> 00:11:47,370
binds to complex one.

244
00:11:47,370 --> 00:11:49,650
The oxidized form
of coenzyme Q will

245
00:11:49,650 --> 00:11:52,140
be reduced first
to a semiquinone

246
00:11:52,140 --> 00:11:55,380
and then to a hydroquinone,
which are located, as shown,

247
00:11:55,380 --> 00:11:58,710
inside the mitochondrial
inner membrane.

248
00:11:58,710 --> 00:12:01,110
We usually draw them
as being free floating

249
00:12:01,110 --> 00:12:04,440
within the membrane, but
that's probably inaccurate.

250
00:12:04,440 --> 00:12:06,270
These co-factors
are probably bound

251
00:12:06,270 --> 00:12:10,140
to physical entities inside the
mitochondrial inner membrane.

252
00:12:10,140 --> 00:12:14,430
The picture also shows FADH2
from the TCA cycle interacting

253
00:12:14,430 --> 00:12:17,430
with complex two, which is
a flavin containing enzyme,

254
00:12:17,430 --> 00:12:20,010
and it will also
transfer its electrons

255
00:12:20,010 --> 00:12:22,230
to the oxidized
form of coenzyme Q,

256
00:12:22,230 --> 00:12:25,190
ultimately to create
the reduced coenzyme

257
00:12:25,190 --> 00:12:28,590
QH2 which is the hydroquinone.

258
00:12:28,590 --> 00:12:31,520
Just as a point of
reference to the TCA cycle,

259
00:12:31,520 --> 00:12:35,900
complex two is also known
as succinate dehydrogenase.

260
00:12:35,900 --> 00:12:38,780
We haven't done fatty
acid oxidation yet,

261
00:12:38,780 --> 00:12:41,300
but there's a step in
fatty acid oxidation

262
00:12:41,300 --> 00:12:45,050
in which an alkane is
converted to an alkene.

263
00:12:45,050 --> 00:12:47,360
The electrons from
that oxidation reaction

264
00:12:47,360 --> 00:12:50,810
go through a flavin
protein called ETF-pre,

265
00:12:50,810 --> 00:12:54,770
for electron transferring
flavor protein, and once again

266
00:12:54,770 --> 00:12:57,320
those electrons
flow into coenzyme Q

267
00:12:57,320 --> 00:13:01,230
to form the reduced
form of coenzyme Q.

268
00:13:01,230 --> 00:13:04,470
Remember when we talked about
the glycerol three phosphate

269
00:13:04,470 --> 00:13:05,120
shuttle?

270
00:13:05,120 --> 00:13:07,350
I mentioned that there's
a mitochondrial membrane

271
00:13:07,350 --> 00:13:11,280
associated glycerol three
phosphate dehydrogenase.

272
00:13:11,280 --> 00:13:14,490
You can see that enzyme at the
top part of the inner membrane

273
00:13:14,490 --> 00:13:16,010
as I've drawn it.

274
00:13:16,010 --> 00:13:18,150
And once again,
flavin in that enzyme

275
00:13:18,150 --> 00:13:20,730
will carry the electrons
into coenzyme Q,

276
00:13:20,730 --> 00:13:25,300
generating reduced form
of the co-factor QH2.

277
00:13:25,300 --> 00:13:27,520
The left part of this
picture pretty neatly

278
00:13:27,520 --> 00:13:31,870
shows how nutrient oxidation
can channel the electrons

279
00:13:31,870 --> 00:13:34,240
into a common mobile
electron carrier,

280
00:13:34,240 --> 00:13:37,000
coenzyme Q. Lots
of different fuels

281
00:13:37,000 --> 00:13:41,130
give up their electrons to
a common electron carrier.

282
00:13:41,130 --> 00:13:43,840
The hydroquinone QH2
will then go and interact

283
00:13:43,840 --> 00:13:47,250
with complex three of the
electron transport chain.

284
00:13:47,250 --> 00:13:49,990
In complex three, electrons
will be transported

285
00:13:49,990 --> 00:13:52,960
through a number of different
electron relay stations

286
00:13:52,960 --> 00:13:55,900
and ultimately be picked
up by cytochrome C, which

287
00:13:55,900 --> 00:13:59,750
is initially in its plus
three oxidation state.

288
00:13:59,750 --> 00:14:02,740
Cytochrome C is reduced
by the single electron

289
00:14:02,740 --> 00:14:04,870
coming through complex three.

290
00:14:04,870 --> 00:14:09,520
In this process its iron is
reduced to its plus two state.

291
00:14:09,520 --> 00:14:11,980
This electron on
cytochrome C then

292
00:14:11,980 --> 00:14:14,710
migrates across
the outer surface

293
00:14:14,710 --> 00:14:16,930
of the inner membrane
of the mitochondrian

294
00:14:16,930 --> 00:14:19,630
to interact with complex four.

295
00:14:19,630 --> 00:14:21,430
When it interacts
with complex four,

296
00:14:21,430 --> 00:14:24,910
the reduced form cytochrome
C gives up its electron

297
00:14:24,910 --> 00:14:27,370
to a copper residue
on the copper

298
00:14:27,370 --> 00:14:31,910
A subunit of complex four.

299
00:14:31,910 --> 00:14:35,810
In the figure, this
complex is called CuA.

300
00:14:35,810 --> 00:14:40,560
the more common name for complex
four is cytochrome C oxidase.

301
00:14:40,560 --> 00:14:45,180
So cytochrome c oxidase
oxidizes is the iron back

302
00:14:45,180 --> 00:14:49,590
to its iron three oxidation
state, then cytochrome C

303
00:14:49,590 --> 00:14:52,050
migrates back to
complex three where

304
00:14:52,050 --> 00:14:54,910
it's able to pick
up another electron.

305
00:14:54,910 --> 00:14:58,390
We can think of cytochrome C as
a mobile electron carrier that

306
00:14:58,390 --> 00:15:01,420
shuttles an electron
along the inner surface

307
00:15:01,420 --> 00:15:04,790
of the mitochondrial
inner membrane.

308
00:15:04,790 --> 00:15:08,150
Looking back at complex four,
or cytochrome C oxidase,

309
00:15:08,150 --> 00:15:11,480
the electrons are
passed from cytochrome A

310
00:15:11,480 --> 00:15:13,550
to a series of other
electron carriers,

311
00:15:13,550 --> 00:15:16,700
and ultimately they flow
into molecular oxygen.

312
00:15:16,700 --> 00:15:20,250
Molecular oxygen is anchored
on one side to heme A3

313
00:15:20,250 --> 00:15:23,110
and on the other
side to copper B.

314
00:15:23,110 --> 00:15:26,470
Oxygen undergoes a four
electron reduction and picks

315
00:15:26,470 --> 00:15:30,910
up four protons along the way
to form two molecules of water.

316
00:15:30,910 --> 00:15:34,150
If the electrons started with
NADH and ends up in oxygen

317
00:15:34,150 --> 00:15:37,690
to form water, you get
220 kilojoules of energy.

318
00:15:37,690 --> 00:15:39,440
And as I said, you
get somewhat less

319
00:15:39,440 --> 00:15:42,910
of your electrons started
out as a reduced flavin.

320
00:15:42,910 --> 00:15:45,070
Now let's look at
panel B. I want

321
00:15:45,070 --> 00:15:47,920
to say a few words at the
outset about proton pumps,

322
00:15:47,920 --> 00:15:51,220
keeping in mind that the
reason electrons were moved

323
00:15:51,220 --> 00:15:55,330
through the electron transport
chain was to power these pumps.

324
00:15:55,330 --> 00:15:59,080
In the lower left part of the
figure, we can see complex one.

325
00:15:59,080 --> 00:16:03,070
The transit of electrons
through complex one from NADH

326
00:16:03,070 --> 00:16:05,830
results in the transport
of four protons

327
00:16:05,830 --> 00:16:09,610
from the mitochondrial matrix
into the intermembrane space.

328
00:16:09,610 --> 00:16:13,330
That is, two electrons
from NADH are transported,

329
00:16:13,330 --> 00:16:15,700
and coincident with
that, four protons

330
00:16:15,700 --> 00:16:19,060
are pumped into the
intermembrane space.

331
00:16:19,060 --> 00:16:20,740
Later we'll see
that complex three

332
00:16:20,740 --> 00:16:23,530
is the location of something
called the Q cycle.

333
00:16:23,530 --> 00:16:25,660
I'm going to cover
the proton pumping

334
00:16:25,660 --> 00:16:28,450
properties of the Q
cycle in some detail

335
00:16:28,450 --> 00:16:30,400
in the next storyboard.

336
00:16:30,400 --> 00:16:32,620
The passage of
those two electrons

337
00:16:32,620 --> 00:16:35,710
through complex three
results in the transport

338
00:16:35,710 --> 00:16:40,960
of an additional four protons
into the intermembrane space.

339
00:16:40,960 --> 00:16:44,320
Lastly, the transit of
electrons through complex four,

340
00:16:44,320 --> 00:16:46,660
the cytochrome C
oxidase, results

341
00:16:46,660 --> 00:16:48,820
in the transport of
another two protons

342
00:16:48,820 --> 00:16:51,750
into the intermembrane space.

343
00:16:51,750 --> 00:16:55,050
Now let's look at panel
C. Adding things up,

344
00:16:55,050 --> 00:16:56,820
if we start with
two electrons coming

345
00:16:56,820 --> 00:17:00,270
from NADH we transport
about 10 protons

346
00:17:00,270 --> 00:17:01,530
into the intermembrane space.

347
00:17:01,530 --> 00:17:05,880
That's enough to make about
three molecules of ATP.

348
00:17:05,880 --> 00:17:09,359
If our electrons start
with FADH2 reduced flavin,

349
00:17:09,359 --> 00:17:12,230
we only transport
about six protons.

350
00:17:12,230 --> 00:17:14,550
That's enough to make two ATPs.

351
00:17:14,550 --> 00:17:17,490
If you remember, making ATP
is only one of the things

352
00:17:17,490 --> 00:17:20,430
that we can do with the
power of the proton gradient.

353
00:17:20,430 --> 00:17:22,140
I mentioned earlier
that we can also use

354
00:17:22,140 --> 00:17:24,800
it to generate heat and motion.

355
00:17:24,800 --> 00:17:27,140
Let me talk for a
minute about why one

356
00:17:27,140 --> 00:17:29,060
would want to generate heat.

357
00:17:29,060 --> 00:17:31,160
Newborn babies are
like small balls.

358
00:17:31,160 --> 00:17:34,410
They have a high
surface to volume ratio.

359
00:17:34,410 --> 00:17:36,320
Their high surface
to volume ratio

360
00:17:36,320 --> 00:17:39,090
makes heat loss a very
significant reality,

361
00:17:39,090 --> 00:17:41,690
and, in fact, a problem
for the newborn.

362
00:17:41,690 --> 00:17:44,390
They have, therefore,
specialized mitochondria

363
00:17:44,390 --> 00:17:47,600
in their neck in an
area called brown fat.

364
00:17:47,600 --> 00:17:50,630
The fat is brown because it
is loaded with highly colored

365
00:17:50,630 --> 00:17:51,950
mitochondria.

366
00:17:51,950 --> 00:17:53,870
These mitochondria
have a protein

367
00:17:53,870 --> 00:17:57,650
that enables the protons pumped
into the intermembrane space

368
00:17:57,650 --> 00:18:00,950
to flow back freely into
the mitochondrial matrix

369
00:18:00,950 --> 00:18:02,840
with the generation of heat.

370
00:18:02,840 --> 00:18:06,530
That is, they don't make ATP in
the brown fat, they make heat.

371
00:18:06,530 --> 00:18:09,680
This helps promote thermal
regulation in the baby.

372
00:18:09,680 --> 00:18:11,780
This is also the
mechanism by which

373
00:18:11,780 --> 00:18:14,240
hibernating animals,
such as a bear,

374
00:18:14,240 --> 00:18:16,790
can maintain body
temperature during the winter

375
00:18:16,790 --> 00:18:19,440
when the bear is hibernating.

376
00:18:19,440 --> 00:18:22,200
This process overall
is called uncoupling

377
00:18:22,200 --> 00:18:24,690
of electron transport,
from the process

378
00:18:24,690 --> 00:18:27,300
that we're going to be
looking at next, oxidative

379
00:18:27,300 --> 00:18:28,470
phosphorylation.

380
00:18:28,470 --> 00:18:31,830
Oxidative phosphorylation
is the process by which

381
00:18:31,830 --> 00:18:35,180
we're going to be making ATP.

382
00:18:35,180 --> 00:18:37,730
Uncoupling is also
a process used

383
00:18:37,730 --> 00:18:40,070
by some flowers
that have to come up

384
00:18:40,070 --> 00:18:42,500
through frozen ground
in the springtime.

385
00:18:42,500 --> 00:18:45,170
For example, the skunk
cabbage and the crocus

386
00:18:45,170 --> 00:18:47,960
are very good at uncoupling
electron transport

387
00:18:47,960 --> 00:18:50,180
from oxidative phosphorylation.

388
00:18:50,180 --> 00:18:53,090
They let the protons in
the proton gradient flow

389
00:18:53,090 --> 00:18:55,370
back across the
mitochondrial inner membrane,

390
00:18:55,370 --> 00:18:58,520
and by doing so these
plants are able to generate

391
00:18:58,520 --> 00:19:00,620
heat that will
allow them to grow

392
00:19:00,620 --> 00:19:02,630
at subfreezing temperatures.

393
00:19:02,630 --> 00:19:07,020
In other words, the plant
itself becomes a little heater.

394
00:19:07,020 --> 00:19:08,850
At this point, let me
give you a little bit

395
00:19:08,850 --> 00:19:12,120
of a preview of how we use
this proton gradient in order

396
00:19:12,120 --> 00:19:13,890
to synthesize ATP.

397
00:19:13,890 --> 00:19:15,750
As we have seen, it
took energy in order

398
00:19:15,750 --> 00:19:19,170
to create a gradient in
which there are protons

399
00:19:19,170 --> 00:19:22,980
in the intermembrane space, and
protons are chemical entities,

400
00:19:22,980 --> 00:19:25,770
so we've created a
chemical gradient.

401
00:19:25,770 --> 00:19:29,190
But also, we're putting a
very high positive charge

402
00:19:29,190 --> 00:19:32,640
density in the small,
enclosed intermembrane space.

403
00:19:32,640 --> 00:19:36,450
So we have also created an
electrochemical gradient.

404
00:19:36,450 --> 00:19:39,960
It is the release of those
gradients that empowers

405
00:19:39,960 --> 00:19:42,420
many of our vital processes.

406
00:19:42,420 --> 00:19:46,350
For a final comment please see
panel D. Peter Mitchell figured

407
00:19:46,350 --> 00:19:49,230
out how the energy in that
electrochemical gradient

408
00:19:49,230 --> 00:19:51,510
could be released and
converted into the energy

409
00:19:51,510 --> 00:19:53,640
it takes to make chemical bonds.

410
00:19:53,640 --> 00:19:56,070
Mitchell's conclusions
serve as the basis

411
00:19:56,070 --> 00:19:58,230
of what is called the
chemiosmotic coupling

412
00:19:58,230 --> 00:20:02,870
hypothesis, and we'll be looking
at that in some detail later.