Burning fats without producing ATP

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Wed Jan 19 16:18:39 EST 2000

Michael Rae wrote:

> When burning fat, mitochondria
> normally produce CO2 as a waste product and ATP as useful output.
> This modification causes them instead to produce just CO2 and heat!
> My understanding is limited, but AFAIK this
> means lots of state 4 activity -- mucho heat, mini ATP, and more
> free radicals than you can shake mtSOD at.

Well, at first sight this seems to be very clearly unsound in detail,
but I haven't seen the full text so I don't know whether the "recent
pilot study" has been published (and, if so, what it actually found).

Taking the biochemistry one step at a time:

- Fatty acid oxidation generates three intermediates which are later
  used to make ATP.  They are NADH, FADH2 and acetyl CoA.  FADH2 is
  recycled via FAD-dependent acyl coA dehydrogenase, thereby putting
  electrons into the respiratory chain at CoQ as stated.  Acetyl CoA
  is fed into the Krebs cycle and thereby recycled with the formation
  of more NADH and also another FADH2, which is likewise recycled by
  reducing CoQ at Complex II (succinate dehydrogenase).  Normally,
  the NADH created at both steps is also fed into CoQ by Complex I,
  and loads of ATP is thereby generated by oxidative phosphorylation.

- In the model presented, Complex I is not used to transfer electrons
  from NADH to CoQ but the other way around -- it recycles CoQ that
  has been reduced by acyl coA dehydrogenase and Complex II, and the
  electrons are given to NAD+ making NADH.  This is OK so far, because
  Complex I can indeed be forced into reverse if the proton gradient
  is enough.  NB: All NADH mentioned so far is inside the mitochondrion.

- There is then the problem of how the NADH is recycled.  In the model
  presented, this is done by reversing the malate/aspartate shuttle.
  The mal/asp shuttle normally ships electrons into the mitochondrion,
  taking them from cytosolic NADH formed by glycolysis and giving them
  to matrix NAD+.  Again, this could be reversed if the redox states
  of the two compartments are adjusted appropriately.

So it's all plausible up to here.  But then:

- The cytosolic NADH must also be recycled.  Here is where the model
  seems to fall apart.  It suggests that the cytosolic NADH re-enters
  the respiratory chain at the CoQ level, which means via the glycero-
  phosphate shuttle (since the malate/aspartate shuttle has been made
  unavailable as explained above).  But that is where they were a few
  steps ago!  Thus, the model seems to entail electrons being fed
  continuously into a loop from which they never escape (CoQ, matrix
  NAD, cytosolic NAD, CoQ, ...).  This obviously isn't sustainable.
  An exit for these electrons would be needed.  One possibility is to
  have some mitochondria working as proposed but others working as
  normal, doing forward electron transport at Complex I and thereby
  consuming the cytosolic NADH generated by the weird mitochondria.
  But it's not clear that much heat would be generated, because all
  the processes involved would be operating close to thermodynamic
  equilibrium: put simply, none of these mitochondria could actually
  be uncoupled, because the weird ones would have to maintain a high
  proton gradient in order to make Complex I go backwards while the
  normal ones would be, well, normal.

However, the more general idea that the supplementation regime in
question may have induced uncoupling of liver mitochondria is not at
all challenged by the above logic.  I see no reason a priori why such
effects should not be inducible, and they would indeed make heat.  The
tricky part is to alter the cells' choice of which fuel to use to make
that heat, i.e. to get them to use fat in preference to dietary sugars.

But coming to free radicals: no, uncoupling certainly does not mean
state 4 activity.  State 4 is when the respiratory chain is working
properly *and* succeeding in making a proton gradient, but then that
gradient is not being consumed by ATP synthase (typically because
there is no ADP to phosphorylate).  So an uncoupled mitochondrion
makes a lot of heat, yes, but not much superoxide because Complexes
I and III are not particularly reduced.

Aubrey de Grey

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