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Energy Metabolism in Mitochondria.

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Energy Metabolism in Mitochondria
By Hans Walter Heldt"]
Mitochondria are separate metabolic compartments within the cell. The functional boundary
of the mitochondrial compartment is the inner membrane. This membrane contains the
enzymatic apparatus for the electron transport and oxidative phosphorylation. The substrate
breakdown cycles are localized in the mitochondrial matrix space. Specific carriers are
responsible for the exchange of ADP, ATP, phosphate, and intermediates of the citric acid
cycle between the matrix space and the extramitochondrial space. The particular importance
of the adenine nucleotide transport to the regulation of the energy metabolism of the cell is
discussed in detail.
Mitochondria occur in the cytoplasm of all aerobic eukaryotic cells. They are the site of cell respiration, and have
therefore been referred to as the "power plant of the cell".
The energy liberated on oxidation of the substrate hydrogen
drives the endergonic synthesis of adenosine triphosphate
(ATP) from adenosine diphosphate (ADP) and orthophosphate (P). This process is known as oxidative phosphorylation[**].The energy liberated on hydrolysis of ATP
to ADP and phosphate covers the energy-consuming processes of the cell ( e . g . mechanical, chemical, osmotic, and
electric work).
There are two important metabolic compartments in the
animal cell, i. P . the extramitochondrial compartment,
which comprises the ground cytoplasm and the nuciear
space, and the mitochondrial compartment. Coordination
[*] Priv.-Doz. Dr. H . W. Heidt
Institut fur Physiologische Chemie und Physikalische
Biochemie der Universitat
8 Munchen 2, Pettenkoferstrasse 12-14a (Germany)
The author's own work in this field was supported by the Deutsche
A comprehensive article on the mechanism of oxidative phosphorylation has been published in this journal by Schatz [l].
of the metabolic processes requires the specific transport of
substrates and products through the membranes that
separate the two compartments. The present report is
concerned with the structure of the mitochondrial compartment. Details of specific transport processes between
the two compartments should provide an insight into the
regulation of the oxidative metabolism.
1. Morphological Structure of Mitochondria
Mitochondria were observed with the aid of the optical
microscope in the middle of the last centurylZ-sl, but a
preciseelucidation oftheirstructure(Fig. 1) became possible
only with the advent of electron microscopyr6-']. A particularly striking feature of mitochondria is the high membrane fraction. They have two types of membrane (Fig. 2),
which differ in their fine structure, lipid composition, and
protein content. The outer membrane surrounds the mitochondrion. The inner membrane extends more or less
densely packed in an endlessly folded or in a tubular
arrangement in the interior of the mitochondria. It has a
very large surface. The mitochondrial matrix that it surAngew. Chem. internat Edit
1 Vol. I1
(1972) / N o . 9
rounds consists of a dense protein gel. Apart from the
membrane phases, therefore, there are two compartments
in the mitochondria, i. e. the intermembrane space between
the outer and the inner membranes and the matrix space.
Characteristic differences between the two membranes are
also found in the lipid composition (Table 1). Thus cholesterol is found mainly in the outei membrane. while
cardiolipin occurs almost only in the inner rnernbrane['2-141.The inner membrane also contains more
protein than the outer membrane. In its lipid composition
the inner membrane resembles a bacterial membrane, and
the outer membrane resembles the plasma membrane.
Table 1. Composition of the outer and inner membranes of mitochondria
from guinea pig liver [ 12, 131
Fig. 1 Mitochondrium from the epididymal epithelium of the mouse.
61000-fold magnification [ 9 ] .
With the aid of the electron-microscope technique of
negative staining['*'], characteristic round "knobs" having
a diameter of about 90 A were observed on the side of the
Outer membrane
Inner membrane
Protein : Lipid
Protein : Cholesterol
1 : 0.829
1 : 0 030
1 . 0.275
1 : 0.0051
Percentage of individual
phospholipids in the
entire phospholipid
Mitochondria multiply by divisionr"- "I. All the mitochondria of an organism are thus descended from the
mitochondria of the egg cell. The deoxyribonucleic acid
differs from
(DNA) present in the
the DNA in the cell nucleus; like bacterial DNA, it has a
cyclic structure. However, the mitochondrial DNA determines only a few proteins that are essential to the genesis
of mitochondrialz2! The synthesis of most of the mitochondrial proteins is controlled by the cell nucleus. It has
been speculated that the aerobic cells arose from symbiosis
between anaerobic cells and aerobic bacteria phagocytized
by them'231.According to this hypothesis, the mitochondrial
outer membrane is derived from the cell membrane, which
has been turned inward by phagocytosis, while the mitochondrial inner membrane is derived from a bacterial
2. Permeation Behavior of Mitochondria
Fig. 2. Scheme of the structure and the fractionation of mitochondria.
inner membrane turned toward the matrix"']. The outer
membrane does not show these knobs. There is now
evidence that these knob-shaped subunits are identical
with the cold-labile ATPase, an enzyme that catalyzes a
step of the oxidative phosphorylation" 'I. However, it is
doubtful whether these subunits that can be seen in the
electron-micrograph are also evident in the intact membrane. I t is possible that they were formed from a preexisting structure on treatment with the reagent. The fact
that these structures are observed only on the inside of the
inner membrane points to the asymmetric structure of this
[*"*I In "negative staining", the sample is spread on a liquid film by
surface tension. Phosphotungstate is then applied to the layer. On
examination in the electron microscope, cell structures give a negative
Angew. Chem. internat. Edit. 1 Vol. I 1 (1972) / N o . 9
Investigations with isolated mitochondria showed that
part of the mitochondrial compartment is freely accessible
to low molecular weight substances, such as inorganic ions,
nucleotides, amino acids, and sucrose. This space is not
accessible, however, to large molecules such as polymeric
sugars or proteins. The size of the s;iace that is accessible to
sucrose can be influenced by the tonicity of the medium.
Under isotonic conditions the sucrose-accessible space
roughly corresponds to one third of the total mitochondrial
solution space. If the isotonic medium is replaced by a
hypotonic medium, the sucrose-inaccessible space increases
at the expense of the sucrose-accessible space. In electron
microscope studies carried out in parallel with this work,
swelling of the matrix space (see Fig. 2) was observed, with
a simultaneous decrease in the intermembrane space. A
comparison of size between the functionally measured and
the morphologically observed spaces showed that the
sucrose-accessible space is identical with the intermembrane
space, and the sucrose-inaccessible space with the matrix
space[24*251. It can be seen from the result that the outer
membrane is permeable to low molecular weight substances,
while the inner membrane is the osmotically active membrane.
important mitochondrial enzymes, which are listed in
Table 2. The oxidation of the substrates and the associated
ATP synthesis take place on or in the inner membrane. The
substrate breakdown processes (citric acid cycle, degradaTable 2. Localization of mitochondrial enzymes [24, 26-41].
3. Localization of Mitochondria Enzymes
Enzymes contained in the mitochondria may be present in
the matrix space o r in the intermembrane space. They can
also be structure-bound components of the inner or outer
membrane. An enzyme of the inner membrane may be
directed toward the matrix space or toward the intermembrane space.
Inner membrane
Respiratory chain
Fatty acyl CoA dehydrogenase
Pyridine nucleotide-transhydrogenase
Dehydrogenases of the citrate cycle
P-H ydroxyacyl-CoA-dehydrogenase
GTP-dependent fatty acid activation
ATP-dependent fatty acid activation
(for short-chain fatty acids)
GTP-AMP phosphate-transferase
lnrermembrane space
Aden ylate-kmase
Nucleoside diphosphate-kinase
Outer membrane
ATP-dependent activation of long-chain
fatty acids
Enzymes of the lecithin synthesis
Two methods are used for the assignment of one of these
positions to a mitochondrial enzyme, i. e. functional
investigations on intact and disrupted mitochondria, and
fractionation of the mitochondria with subsequent measurement of the enzyme activities in the fractions.
The functional investigations are based on the fact that the
intermembrane space is freely accessible to substrates and
nucleotides. The matrix space, which is not freely accessible,
contains the mitochondrial nucleotides and Mg2+ ions,
among other things. The inner membrane is impermeable
to nucleotides, apart from a specific transport for adenine
nucleotides, which will be discussed later. This transport is
inhibited by atractyloside (Section 7). The localization of
an enzyme inside the mitochondria can be determined e.g.
by measurements of the reactivity with intramitochondrial
o r extramitochondrial nucleotides, sensitivity to atractyloside, and dependence on added Mg2+ ions.
The fractionation of the mitochondria is based on specific
opening of the outer membrane. The soluble enzymes of
the intermembrane space are liberated and are found in
the supernatant. A scheme of this process is shown in
Figure 2. One method for selective rupture of the outer
membrane is treatment of the mitochondria with hypotonic
241. Since the inner membrane is osmotically
active, the matrix space swells in the hypotonic medium,
and the inner membrane presses against the outer membrane and bursts it open.
Another method of rupturing the outer membrane selectively makes use of the fact that cholesterol occurs mainly
in the outer membrane. It is well known that cholesterol
forms a compound with digitonin. The addition ofdigitonin
to mitochondria binds the cholesterol of the outer membrane and causes the membrane to break open[26-281.The
fragments of the outer membrane, which are mostly in the
form of vesicles, can be ,separated by centrifugation in a
density gradient. The bare mitochondria, consisting of the
inner membrane and the matrix enclosed by it, remain
behind. In these bare mitochondria the folds of the membrane turn outward. Treatment with ultrasonic radiation
leads to destruction of the inner membrane. The membrane
fragments form small vesicles, which can be separated
from the soluble proteins of the matrix space by centrifugation.
The broad lines of the organization of the mitochondrial
metabolism are recognized from the localization of some
tion of fatty acids) are localized in the matrix space. The
reduction equivalents resulting from these processes (in
the form of NADH, succinate, or acyl coenzyme A) diffuse
to the inside of the inner membrane, where they are oxidized.
The ATP synthesis coupled with the respiratory chain
takes place on the inside of the inner membrane, and the
ATP formed passes into the matrix space. Carefully prepared bare mitochondria accordingly exhibit all the essential properties of intact mitochondria[261. On the other
hand, the enzyme activities of the intermembrane space
(some of which also occur outside the mitochondria) and
the membranes of the outer membrane appear to have
more of an accessory importance.
4. Properties of the Inner Membrane
From the functional standpoint, the intermembrane space
may be regarded as belonging to the extramitochondrial
compartment. The partition separating the mitochondrial
and the extramitochondrial metabolic compartments is the
inner membrane. Through this membrane the substrates
of the mitochondrial oxidation, mainly pyruvic acid and
fatty acids, as well as orthophosphate and ADP must pass
into the matrix space, and the product ATP must be
released from the mitochondria.
Closed membranes are fundamentally impermeable both
to cations and to anions. Membranes present much less
hindrance to the penetration of undissociated acids or
bases, since these substances can dissolve to some extent in
the lipid layer ofthe membrane. It is thus possible for anions
Angew. Chem. internat. Edit. / Vol. I 1 (1972) / No. 9
specific carrierst4*- 531. The dicarboxylic acid carrier transports malate and succinate in exchange with these dicarboxylic acids or with phosphate. The transport of citrate
and isocitrate by the citrate carrier and the transport of
cl-ketoglutarate by the a-ketoglutarate carrier occurs in
exchange with dicarboxylic acids. There is also evidence
of a specific transport of glutamate.
and cations to pass through the membrane via the undissociated molecules that exist in equilibrium with them. This is
probably true of a number of monocarboxylic acids. In the
cases of dicarboxylic and tricarboxylic acids and phosphoric
acid, on the other hand, thedissociation equilibria in neutral
solution lie so far on the side of the anions that membranes
are practicaily inpermeable to these substances[42J.
In connection with the permeation properties of membranes
it is interesting to note that the most important substrates
of the mitochondria i. e. pyruvic acid and the fatty acids,
are monocarboxylic acids. On the other hand, the intermediates of the mitochondrial substrate breakdown cycles
(citric acid cycle and oxidation of fatty acids) are dicarboxylic or tricarboxylic acids or derivatives of coenzyme A
(a compound containing phosphate), which cannot diffuse
freely through the inner membrane. The same is true of the
pyridine nucleotides, which take part in the substrate
breakdown, and of the adenine and guanine nucleotides,
which take part in the energy conservation.
palmit y L carnitine
pa Imitate
+ pyrophosphate
X ~ . ~ ~CoAl ~ c a r n i t i n epalmityl - CoA-p oxidation
transferase Il
Fig. 3. Scheme of the activation of long-chain fatty acids and of the
transport of activated fatty acids into the matrix space [4S].
5. Transport of Substrates
Both the pyruvic acid and the short-chain fatty acids can
probably pass through the inner membrane without special
carrierst4’]. Recent findings concerning the occurrence of
a special carrier for the pyruvate anion in the inner membranet431require further investigation.
Whereas the short-chain fatty acids are activated ( i e .
bonded to coenzyme A) in the matrix space, the activation
of the long-chain fatty acids, such as palmitic acid, occurs
on the outer membrane or on the endoplasmic reticThe mitochondria are thus faced with the
problem of bringing the activated fatty acids into the
matrix space through the inner membrane, which is impermeable to coenzyme A and its derivatives. This is achieved
by a special transport mechanism, of which all the details
have not yet been clarified. Three observations are important to discussions about a possible reaction course
(Fig. 3): a) Carnitine [3-hydroxy-4-(trimethylammonio)
butyrate] is required for the oxidation of ~ a l m i t a t e ‘ ~ ~ ] .
b) Neither carnitine nor coenzyme A or its esters can pass
through the inner membranef4’. 461. c) Two different
acylcoenzyme A-camitine transferases have been discovered, one of which is bound in the inner membranet4’].
The acylcoenzyme A outside the inner membrane is
assumed to be converted into acylcarnitine by the external
transferase (I), with liberation of coenzyme A. The transferase in the inner membrane (11) is thought to be arranged
~ e c t o r i a l l y [ ~i. ~
, bonding sites for carnitine and
acylcarnitine are directed outward, and the bonding sites
for coenzyme A and acylcoenzyme A toward the matrix.
According to this scheme, acylcarnitine passes from outside
to the inner membrane, and the acyl residue is “handed
through” and reacts with the mitochondrial coenzyme A
on the inside of the membrane. This would mean that a
functional unit exists here between the chemical reaction
and the directed transport through the membrane.
The inner membrane is impermeable to the intermediates
of the citric acid cycle. This impermeability is overcome by
A n y e w Chem. internat. Edir. / Vol. I 1 (1972) I No. 9
The transport of malate is important to gluconeogenesis.
The initial step of this metabolic chain, i. e. the carboxylation of pyruvate, takes place in the matrix spacet4’]. The
resulting oxalacetate can be transported out of the mitochondria as malate after reduction. The further synthesis
steps of gluconeogenesis then take place outside the
The transport of citrate plays a part in l i p o g e n e ~ i s ~The
starting material for the synthetic chain of lipogenesis is
acetyl-coenzyme A, which is formed in the mitochondria
e.g. from pyruvate. Since the fat synthesis takes place
outside the mitochondria, the acetyl-coenzyme A must be
carried out of the mitochondria. Since the inner membrane
is impermeable to coenzyme A and its thioesters, indirect
transport occurs. Acetyl-coenzyme A condenses with
oxalacetate in the mitochondria to form citrate, and this
is transported into the extramitochondrial space by the
citrate carrier, where it is converted back into acetylcoenzyme A and oxalacetate.
6. Transport of Phosphate
The transport of phosphate by the phosphate carrier takes
place in exchange with hydroxide ions or as a co-transport
with protons[42.49, 551. These possibilities cannot be
distinguished experimentally. The transport is inhibited by
very low concentrations of compounds that block SH
groupst56-581. The phosphate carrier thus contains free
SH groups. The phosphate required for the oxidative phosphorylation can pass into the matrix space through the
phosphate transport. Since the transport of phosphate
takes place without exchange with anions, apart from
hydroxide ions, whereas the transport of dicarboxylic acids
occurs in exchange with phosphate and the transport of
tricarboxylic acids in exchange with dicarboxylic acids, the
phosphate transport has a key function for the uptake of
dicarboxylic and tricarboxylic acids into the mitochondria.
7. Transport of Adenine Nucleotides
A carrier transports the ADP into the mitochondria and the
ATP formed out of the mitochondria (Fig. 4). This carrier
is specific for ADP and ATP. AMP, guanine, and uracil,
cytidine, and pyridine nucleotides are not t r a n ~ p o r t e d ” ~ ~ .
The transport is an obligate exchange: for each molecule of
adenine nucleotide transported in, another must be trans-
mitochondria in the presence of substrate. After the ADP
had been phosphorylated and the state of respiratory
control had been reached, the mitochondria were centrifuged from the medium through a silicone layer into
perchloric acid[661. It was thus possible to measure the
nucleotide concentrations in the matrix space and in the
surrounding medium in the same experiment (Table 3).
Table 3. Phosphorylation potential AG‘ of ATP in mitochondria and
in the medium in the state of respiratory control (20°C) [65].
A G = A G O- R T x In([ATP]/[ADP] x [Phosphate])
AGO = - 8 8 kcal,’mol[70].
0 48
Fig 4. Functional scheme of the adenine nucleotide transport
ported out. The carrier probably cannot pass through the
membrane in the uncharged state[601.In this way the total of
mitochondrial adenine nucleotides remains constant. The
affinity of the carrier is very high. Half of the maximum
transport rate is reached at an ADP concentration outside
the mitchondrion of only 12 x
M [ ~ * ] . Atractyloside.
a plant glycoside from the mastic thistle (Atractylis gummifera) and bongkrek acid, an antibiotic, are specific inhibitors of the adenine nucleotide transportF6’-631. Both
substances are therefore very powerful poisons.
The specificity of the adenine nucleotide carrier is different
for the two transport directions. There are no measurable
differences between ADP and ATP for the outward transport. For the inward transport, on the other hand, ADP is
strongly favored over ATP. However, this is true only of
intact mitochondria, in which a coupling exists between the
transport of electrons by the respiratory chain and the ATP
synthesis. If this coupling is eliminated by “uncouplers”
(e.g. dinitrophenol), ADP is no longer favored for the
inward transport; ATP is then transported as readily as
ADPfS9,641. It can be concluded from these findings that
the preference for the transport of ADP requires the consumption of energy. This energy is supplied by the respiratory chain. It has not yet been established in detail how the
transport is influenced by the energy. It is assumed that
through the transport of electrons by the respiratory chain,
a potential is built up across the inner membrane. Since
ATP carries one negative charge more than ADP, a membrane potential could allow a discrimination against the
transport of ATP through the inner membrane1421.
The asymmetry in the specificity of the transport of adenine
nucleotides leads to an asymmetric distribution of ADP
and ATP on the two sides of the membrane. The ATP/ADP
ratio is greater outside the mitochondria than inside[651.
To check this, ADP was added to a suspension of aerobic
The ATP/ADP ratio was found to be about 7 times as high
in the medium as in the matrix space. With the aid of the
measured phosphate concentrations it is possible to calculate the free energy of the hydrolysis of ATP, which is
also known as the phosphorylation potential, for both
spaces. The phosphorylation potential found for the ATP
in the medium is 2.3 kcal/mol more negative than for the
ATP in the matrix space.
Though the phosphorylation potential in the mitochondria
certainly cannot be calculated exactly in this way, it can be
seen that the energy consumption required for the release
of the ATP from the mitochondria may be considerable.
This has important consequences for the ratio of the ATP
formed to the oxygen consumed (P/O ratio) in the cell. It
is well known that a P/O ratio of 3 is found in mammalian
mitochondria for substrates that enter the respiratory chain
at the NADH stage, and a P/O ratio of 2 for substrates that
attack at the flavoprotein, e.g. succinate. However these
figures are obtained only if the ATP/ADP ratio outside the
mitochondria is artificially kept low. This can be achieved
by addition of glucose and hexokinase to the medium ; the
terminal phosphate residue of the extramitochondrial ATP
is then transferred to glucose. Lower P i 0 values are observed without this “ATP trap”, since part of the energy gained
in the respiratory chain must be used up to release the
ATP from the mit~chondria[~’].
The question arises whether the differences between the
ATP/ADP ratios inside and outside the mitochondria in
the test tube also occur in the living cell. To answer this
question, the reactions occurring in a perfused liver were
stopped by sudden cooling to - 195“C, and the frozen liver
was freeze-dried and then homogenized in heptane. Mitochondria and nonmitochondrial cell material were separated by centrifugation of the homogenate in a heptanecarbon tetrachloride density gradient, and the adenine
nucleotides were determined enzymatically in the resulting
fractions. This experiment showed that the ATP/ADP
ratio in the intact cell outside the mitochondria was more
than 5 times as high as in the mitochondria[681.Agreement
with the results found for isolated mitochondria is therefore good.
Angew. Chem. internat. Edit. 1 Vol. 11 (1972)
1 No. 9
8. The Importance of the Adenine Nucleotide Transport to the Energy Metabolism of the Cell
The living cell tends to maintain its ATP concentration at a
constant value. A decrease in the ATP concentration on
consumption of ATP can be offset for a short time by ATP
reserves. Such reserves consist of the ADP that is in equilibrium with ATP and AMP in the presence of adenylate
kinase, and creatine phosphate:
.1dcn\. 1;,1<3-
. A T P + AhlP
ADP + C r e a t i n e p h o s p h a t e
A A T P + Creatine
These systems may be regarded as ATP buffers. The ATP
consumption is ultimately compensated by ATP synthesis.
Tn the aerobic metabolism of glucose, 95% of the ATP
formed is synthesized in the mitochondria. Oxidative phosphorylation is thus the main source of the ATP in the cell.
The ADP-concentration in the matrix space controls
respiration. The higher the concentration, the higher the
respiration rate and hence also the rate of ATP synthesis.
However, half of the maximum rate of oxidative phosphorylation is reached only when about half of the adenine
nucleotide in the matrix space is in the form of ADPr691.
If the adenine nucleotide concentrations inside and outside
the mitochondria were equal, a relatively large decrease in
the cellular ATP concentration would be required to cause
a fairly large increase in respiration. In this case the “ATP
buffer” would be exhausted before increased ATP synthesis
could occur. It has been observed for muscle, however,
that after stimulation, a pronounced increase in respiration
occurs before the creatine phosphate is exhausted[711.The
adenine nucleotides transport evidently plays an important
part here. Because of the energy-dependent preference for
the transport ofADP into themitochondria, a small increase
in the ADP concentration in the extramitochondrial space
leads to a marked increase in the A D P concentration in the
matrix space, with the result that the ATP synthesis in the
mitochondria is stimulated. The energy consumption
required for the adenine nucleotide transport could thus
be regarded as a contribution to the maintenance of a
constant cellular ATP concentration.
Received: May 21, 1971 [A 898 IE]
German version: Angew. Chem. 84,792 (1972)
Translated by Express Translation Service, London.
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Self-organization of Molecular Systems and Evolution of the
Genetic Apparatus[**]
By Hans Kuhn[*l
The aim of the work described in this report is to find pathways leading to self-organization
of molecular systems. The idea is not to trace the historical pathway of evolution but to describe a model whose experimental verification should help to clarify the important principles
of evolution. The difficulty of accepting the origin of living organisms as a physico-chemical
phenomenon and the deeply rooted notion that a system of such complexity as the genetic
apparatus could never be the outcome of processes based solely on the known laws of physics
have influenced philosophical thinking very strongly. This study is also intended as an attempt
to overcome this psychological problem by systematic pursuit of a model pathway composed
of many, readily comprehensible steps. A process thus becomes understandable which cannot
be grasped as a whole, and is therefore alien to our conceptual habits.
1. Presentation of the Problem
A veil of uncertainty still surrounds the formation of the
first biological systems from which the great variety of
organisms developed during the further course of evolution['-61. Such systems must already have had the property
of self-reproduction, and this can only have been possible
if they were of considerable complexity. They must have
had a mechanism employing very sophisticated strategies,
comparable with those of the genetic apparatus of presentday organisms. How could this kind of system develop?
Do the laws of physical chemistry suffice to explain this
process or do we have to postulate principles that are still
unknown? Let us suppose that the origin of life can be
described as a physico-chemical process : does this process
take place wherever appropriate conditions are to be found
or is it a process of extremely low probability which
nevertheless happened to take place on earth?
Prof. Dr. H. K u h n
Max-Planck-lnstitut fur Biophysikalische Chemie
34 Cottingen-Nikolausberg. Postfach 968 (Germany)
[**I Extended version of a lecture given at Marburg on January 29,
The basic hypothesis of the following is that the origin of
life is a physico-chemical process which occurs by necessity
under appropriate conditions. The following two problems
then require solution: first of all, a basis has to be given
for the hypothesis. If it is correct, the intuitive reluctance
to accept it is a psychological difficulty, and consequently
the second task is to overcome this difficulty.
Possibilities for the formation of self-organizing systems
have been considered by the mathematicians v. N e ~ m a n n [ ~ ] ,
Turing[*],and more recently Ulam[']. The search for general
principles that are important for the evolution of selforganizing systems is the topic of studies by Prigogine"']
and Katchalsky[' and particularly of Eigen s comprehensive theory on the self-organization of matter and the
evolution of macromolecules['21.
We proceed in a somewhat different manner: we try to find
a model pathway offering a plausible route for the formation of a mechanism Iike the genetic apparatus. The model
pathway consists of a number of small steps. Each step
follows from the preceding one as an answer to the question of which type of behavior seems most likely. Possible
ways are invented, the time requirement is estimated, and
the fastest possibility is chosen as the next step (Fig. 1).
Angew. Chem. internat. Edit. Vol. 11 (1972)
1 No. 9
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metabolico, energy, mitochondria
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