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Fig.
11.37
). But the realistic molecular mechanisms accomplishing such com-
plex molecular processes were left undefined.
3. The respiratory enzyme system catalyzing Process 1 and the reversible ATPase
system catalyzing Process 2 are coupled through the mediation of the common
chemical species, i.e.,
protons
, which are generated from respiration (upper box) and
consumed by the ATP synthase (lower box) through as yet unknown mechanisms.
I have long expressed my doubt about the validity of the chemiosmotic hypoth-
esis (despite the seemingly universal acceptance of the chemiosmotic theory by
biochemistry textbook writers around the world), because it does not provide any
realistic theoretical insights into the possible molecular mechanisms underlying
oxidative phosphorylation (Ji 1974b, 1979, 1991). Even if the chemiosmotic
hypothesis proves to be theoretically correct, it cannot represent a
universal
princi-
ple of
biological energy coupling
because there are membrane-independent (and
hence
non-osmotic
) energy-coupled processes in biology, including
muscle con-
traction
,
molecular motors
moving cargoes along cytoskeletal tracks in the cytosol,
and the
tracking of RNA polymerase
along DNA during transcription. In Ji (1991,
pp. 60-61), I wrote:
...
The chemiosmotic hypothesis of oxidative phosphorylation proposed by P. Mitchell in
1961 (Nicholls 1982; Skulachev and Hinkle 1981) postulates that ATP synthesis is driven by
the electrochemical gradient of protons across the inner mitochondrial membrane which is set
up by respiration; in other words, in Mitchell's model the generation of the transmembrane
electrochemical gradient of protons driven by respiration precedes the phosphorylation
reaction. However, according to the Madisonator [i.e., Fig.
11.36
], the respiration-driven
generation of the transmembrane proton gradient (step 3 in Fig. 1.3) [which is Fig.
11.36
here] and the phosphorylation reaction (steps 5 and 6) are parallel events that are driven by a
common free energy precursor generated from respiration, namely conformons (see steps 1
and 2). The primary biological role of the active transport in mitochondria is thought to be not
the synthesis of ATP as P. Mitchell assumes but most likely the
communication between
mitochondria and metabolic events
going on in the cytosol. If this interpretation turns out to
be correct, then the phenomenon of the proton gradient-driven ATP synthesis, well-known in
the literature, may have no general biological significance in mitochondria, except perhaps
that such a process may contribute to the survival of cells under anoxic conditions when
the cytosolic pH drops due to the accumulation of lactate produced by anaerobic glycolysis
and that the resulting transmembrane proton gradient may drive ATP synthesis according to
the chemiosmotic mechanism of P. Mitchell. (emphasis added)
R. J. P. Williams (1969) is another critic of the chemiosmotic coupling concept.
His criticism, aired from the very beginning of the chemiosmotic conception, is
based on the consideration of thermodynamic efficiency, which I find persuasive as
discussed in (2) below. The following are my specific criticisms against the
chemiosmotic hypothesis:
1. Mitchell's proposed mechanism for effectuating respiration-driven proton translo-
cation across the mitochondrial membranes is based on what he calls
vectorial
metabolism
or
anisotropy of membrane protein organization
(Mitchell 1961). This
idea seems insufficient to account for oxidative phosphorylation, because struc-
tural organization alone, no matter how asymmetric, cannot cause an asymmetric
transport of the products of chemical reactions without dissipating requisite free
