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(CANCER
RESEARCH
35, 3332-3335, November 1975]
Is There a Role for Mitochondrial Genes in Carcinogenesis?'
Henry D. Hoberman
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461
development of cancer, is heritable, since the damaged
respiratory apparatus is a part of the mitochondrion, which
Although defective respriration is not characteristic of all is itself an autonomous organelle. (c) Dedifferentiation
is
tumors, recent comparative studies on the ultrastructure of the result of the replacement of respiration, which depends
normal and tumor cell mitochondria
indicate that in on the structural integrity of the mitochondrion, by fermen
malignant cells mitochondria deviate from normal not only tation, the reactions of which are catalyzed by enzymes in
in relative abundance but also in the size, form, density, and solution (state of disorganization).
frequency of appearance of lesions. Normal and abnormal
It does not do Warburg justice that most students of
mitochondria may populate the same cell, suggesting that
oncology have rejected all of his postulates because of their
there may be a gradation in respiratory deficiency depend
disagreement with 1 (the 1st). While perhaps based less on
ing on the proportion of normal to abnormal forms.
fact than on the innate suitability of the concept to his
Recent advances in mitochondrial genetics suggest that
overview of carcinogenesis, his idea of an association of a
aberrant mitochondria
may be formed as a result of the defective, heritable mitochondrion with cancer may, in due
presence of an abnormal mitochondrial genome. In analogy
time, turn out to be not entirely farfetched.
with the petite mutant of certain strains of yeast, animal
In regard to the question of energy metabolism
of
cells may be transformed by treatment with dyes that alter
neoplastic as compared with normal cells, there persists an
the structure of their mitochondrial
DNA, so that their
impression, despite recurrent controversy, of the existence
mitochondria
also become deficient in enzymes of the of a genuine difference of respiratory function between the 2
respiratory chain. Whether nutritional or other deficiencies kinds of tissues. In his comprehensive
review of the
are mutagenic with respect to mitochondrial DNA of glycolysis and respiration of tumors, Aisenberg summarizes
animal cells is not known; nor is it known whether
his views, in part, in the statement that “the
most striking
mitochondrial
mutagenesis
is causally involved in car
property of neoplastic energy metabolism remains the high
cinogenesis. New knowledge of cytoplasmic genetics and of glycolytic rates of slices of tumor tissue,―at the same time
mitochondrial DNA and membrane structure and dynamics
recognizing that a high rate of glycolysis is not uniquely
should encourage investigations aimed at examining the restricted to tumor tissue (1).
possible role of mitochondrial genes in neoplastic transfor
In a more recent survey of the same field, Wenner (36),
mation.
while emphasizing that the energy derived from glycolysis
by minimal deviation tumors neither predominates nor even
comprises an appreciable proportion of the total energy
No one can give thought to the subject of mitochondrial
generated by the cell, concluded that vehement glycolysis,
metabolism
in relation to cancer without recalling the
aerobic as well as anaerobic, remains I of the striking
theory of carcinogenesis proposed about 20 years ago by
biochemical properties of the cancer cell, particularly in the
Otto Warburg (33-35). Although much of what he held to
rapidly growing tumor.
be true is presently given little credence, one of his convic
More recently, attention has been directed to properties
tions, namely, that the respiration of tumor tissue is defec
of tumor cell mitochondria that can be visualized under the
tive, still remains viable, as judged by the number of re
electron microscope rather than to their biochemical char
ports, both pro- and con-Warburg, appearing in the cancer
acteristics. Bernhard, in his review of this field of investiga
literature.
tion (3), although underlining the great variability of
While mention of Warburg in relation to cancer usually
mitochondria
in tumor as compared with normal cells,
calls to mind his concept of the energy metabolism of
formed the general impression that cancer cells have fewer
tumors, it should be noted that Warburg's belief that tumor
mitochondria than do their normal counterparts, their
respiration was defective was only 1 of 3 related ideas on
number decreasing with development of the tumor. He
carcinogenesis. I have taken the liberty of paraphrasing his
also noted numerous swollen mitochondria. While recogniz
main thoughts on this problem in the following sentences.
ing that mitochondrial swelling might somehow be second
(a) Due to damage to its respiratory apparatus, the tumor
ary to intensive growth, Bernhard found the same lesions in
cell adapts to the life of an anaerobic organism. (b) The
cells that were well preserved in all respects and presumably
defect in respiration, which is the specific stimulus to the
were actively growing at the time of fixation. Summarizing
his overall impressions of tumor cell mitochondria,
Bern
1 Presented
at the
Conference
on Nutrition
in the Causation
of Cancer,
hard was struck by the extraordinary variation in number,
May 19 to 22, 1975, Key Biscayne, Fla. Aided by USPHS Grant CA
size, form, density and frequency of lesions that they pre
03651from the National CancerInstitute.
Summary
3332
CANCER RESEARCH VOL. 35
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Mitochondria
sent. He pointed to the necessity, therefore, of critical mor
phological control of mitochondrial pellets prepared for
biochemical studies. These observations as well as similar
observations
recorded by others (4, 23, 24) strongly
suggest
that procedures used to isolate mitochondria from normal
tissues, when applied to tumor tissue, may eliminate those
of greatest biochemical interest. In any case, when consid
eration is given to the observed pleomorphism of tumor cell
mitochondria and to the lesionsthat have beennoted, there
would seem to be little reason to expect uniformity of en
ergy metabolism among all types of neoplasms.
As has already been indicated, 1 of Warburg's beliefs,
namely, that mitochondria are autonomous organelles, de
serves greater attention than it has received to date. War
burg derived support for his view that mitochondria
are
heritable structures from plant genetics, a view that early on
recognized the existence of cytoplasmic genes. Among the
workers whom Warburg cited for special mention were M.
W. Woods and H. G. DuBuy of the National Cancer Insti
tute, who found, in leaves of a variegated species of Nepeta
cataria (catnip), mixed cells containing multiple mitochon
drial types (37). Most significantly,
the mitochondrial
phenotypes were transmitted to progeny by non-Mendelian
inheritance. Borrowing heavily from Woods and DuBuy,
who were themselves convinced of the pertinence of their
studies to cancer ( I I ), Warburg proposed that, once a
mitochondrion was damaged, it remained so, transmitting
its defect to progeny (presumably mitochondria),
just as
would occur, he asserted, in the case of a damaged nuclear
gene. Although there would seem to be reason to allow the
speculation that cancer cells, through defects in mitochon
drial structure, may have nonfunctioning respiratory chains,
the question whether such defects are transmissible is as
yet highly conjectural.
My assignment
as a participant
in this meeting is
specifically to consider whether, due to aberrations caused
by a change of nutritional conditions, mitochondria
can
play a role in carcinogenesis. Without at this time speculat
ing on that question, there can be no doubt that mitochon
drial function per se is sensitive to the withdrawal from the
diet of certain vitamins and trace elements. An extreme ex
ample is the effect of a lack of dietary copper. In this condi
tion the loss of activity of cytochrome oxidase is so severe
that liver mitochondria of animals killed at the height of the
deficiency are unable to respire (14). Although iron depri
vation, because of the obligatory role of heme and non-heme
forms of iron in electron transport, would also be expected
to embarrass electron flow, dietary restriction of iron by
curtailing the synthesis of hemoglobin
rather than of
iron-containing
enzymes of the respiratory chain so limits
the life-span of experimental
animals that death occurs
before loss of respiratory function is noted (5).
Turning to the vitamins, the nature of experimentally
induced abnormalities of mitochondrial metabolism is pre
dictable from the known function of the coenzymes of which
the vitamin is a precursor. Thus lack of riboflavin, a precur
sor of flavin mono- and dinucleotides, has been shown to
bring about a slowing of oxidation of NADH and succinate
by mitochondria of deficient animals (7). A lack of dietary
and Carcinogenesis
pantothenate
causes a deficiency of CoA so that, under
standably, carbohydrate and fatty acid oxidation, as well as
turnover of the citrate cycle, are severely disrupted (22).
Whether these or other impairments
of mitochondrial
function have a potential for carcinogenesis brings us back
to the main question. Taking into account what has already
been said about specific biochemical and ultrastructural
features of tumor cell mitochondria, it would seem less
probable that aberrant mitochondria are capable of stimu
lating cell growth and division than that healthy mitochon
dna normally exert a controlling influence on cell growth
and division. Be that as it may, any theory of carcinogenesis
that includes a role for mitochondria must take into
consideration the possibility that, for cancer to develop as a
result of mitochondrial
impairment,
the defect must be
mutagenic for the mitochondrion.
A changeof nutritional environment of a cell may reveal
the existence of mutant forms of mitochondria.
This is
exemplified by the appearance of a population of mutant
organisms, containing abnormal mitochondria,
when cells
of Saccharomyces cerevisiae, a facultative anaerobic strain
of yeast, are changed from growth on a medium containing
glycerol or ethanol as a carbon source to a medium
containing
glucose or other fermentable
sugar. While
growth of the organism on alcohol or glycerol is oxygen
dependent, growth on glucose-containing
media takes place
at the expense of fermentative energy. When cells of S.
cerevisiae are plated on a soft nutrient medium containing
glucose, colonies are formed among which are some smaller
than the majority. The smaller colonies (petites), on under
going mitotic division, yield progeny having the same
appearance
as the parents, as well as other heritable
properties, among which is a defect of respiratory function.
The loss of respiratory function has been found to be due to
mitochondria that lack the capacity to synthesize or assem
ble polypeptides that are precursors of cytochrome oxidase,
cytochrome b, cytochrome c1 , and the rutamycin-sensitive
ATPase of oxidative phosphorylation.
Without these con
stituents of the respiratory chain, petite mutants do not
respire or carry out oxidative phosphorylation (I 2, 17, 18).
As detected simply by a change of one carbon source for
another, the petite mutation is spontaneous yet occurs with
a frequency that can be orders of magnitude greater than
rates ofspontaneous nuclear mutations. Under certain other
conditions the rate of mutation can reach 100%. Thus
Ephrussi et a!. (13) found that acriflavin, an acridine dye,
could transform an entire population of cells to the petite
form.
Of special significance
was the observation
that the
yield of mutant colonies was the same whether the parent
cells were of a haploid or diploid strain. This independence
of the effect of the dye from gene dosage provided strong
evidence from which it was concluded that the mutation was
not that of a nuclear but of a cytoplasmic gene. In S.
cerevisiae, cytoplasmic genes are contained in the mitochon
drion, the genetic message being encoded in the mitochon
drial DNA.
The frequency of mitochondrial
mutation can be in
creased even when cells are metabolizing under aerobic con
ditions. Mass formation of petite mutants of S. cerevisiae
NOVEMBER 1975
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3333
H. D. Hoberman
was accomplished by preventing mitochondr'al synthesis
of ATP by inhibiting respiration with cyanide or antimycin
A, while simultaneously blocking uptake of glycolytically
formed ATP with an appropriate
inhibitor (bongkrekik
acid). These results were interpreted to indicate that the
constant presence of ATP within mitochondria is essential
to normal replication of mitochondrial
DNA (30). An
alternative interpretation
is that interference with energy
utilization in mitochondria may be mutagenic for mitochon
drial DNA.
In the presence of ethidium bromide, a phenanthrid@ne
dye that intercalates between complementary
bases in du
plex DNA, mitochondrial
DNA synthesis is selectively in
hibited and preexisting mitochondrial DNA is progressively
degraded (15). The petite mutation is thereby enhanced to
the extent that mass formation of the respiration-deficient
mutant occurs. In a concentration that readily enhances
production of mitochondrial mutants, ethidium bromide is
without effect on the synthesis or degradation of nuclear
DNA. This selective action of the dye has now been shown
also to be expressed in animal cells.
When mouse L-cells were exposed to a concentration of
ethidium bromide, 1 @tg/ml, the cell content of cytochrome
oxidase and cytochrome b declined (29). The mitochondria
enlarged and were noted to have fewer cristae; those that
remained appeared abnormally organized. Both normal and
abnormal mitochondria were seen in the same cell, suggest
ing not only a difference among mitochondria in their
sensitivity to the dye but also suggesting that mitochondrial
mutation is an effect on individual organelles rather than
on the cell as a whole. The latter inference would also be
consistent with the observation that the loss of mitochon
drial cytochromes is partial and for the fact that the action
of ethidium bromide on mouse L-cells is reversible. Thus
while damaged mitochondria could not replicate, those
that were undamaged would be capable of doing so after re
moval of the dye. This uneven susceptibility of mitochon
dna to a mutagen may be an explanation for the survival
of animal cells that have been exposed to such agents. Un
like the petite mutant that, when its mitochondria are no
longer functional, readily adapts to an anaerobic life, ani
mal cells may survive only when loss of mitochondrial
viability is incomplete. In the sense that Warburg intended,
there would seem to be no facultative anaerobes among
animal cells.
Effects of ethidium bromide on 1-leLa cells (26), Chang
liver cells (16), regenerating liver (10), and the like are
similar to those to which attention has already been called,
i.e., confirmatory of changesin the concentration of mito
chondrial cytochromes following from mutagenic effects of
the dye. In all instances, effects of ethidium bromide on
mitochondrial but not nuclear DNA were observed.
In the biogenesis of mitochondria, 2 separate and distinct
genetic systems are involved in the synthesis and assembly
of polypeptide constituents of the membranes and enzyme
systems, namely, that of the nucleus (cytoplasmic system)
and that of the mitochondrion itself. Which mitochondrial
components are encoded in nuclear DNA and which in
nitochondrial DNA is presently uncertain. In animal cells,
3334
mitochondrial DNA consist of circular, double-stranded
light and heavy chains of supercoiled molecules having a
molecular weight of 9 to 10 million daltons (19, 28, 32). It
has recently been estimated that, in the HeLa cell, genes so
far identified on mitochondrial DNA account for about 25%
of the potential information contained in the 5-nm-long
DNA molecule (2). Of singular interest is the fact that, on
animal cell and yeast mitochondrial DNA, genes have been
identified that encode for tRNA's that almost without
exception are specific for the hydrophobic amino acids (9).
It is, therefore, no wonder that all proteins synthesized on
mitochondrial ribosomes have so far been found to belong
to the class of hydrophobic proteins associated with the
inner mitochondrial membrane (6).
In petite mutants that have grossly altered or no mito
chondrial DNA, it is found that mitochondria-like struc
tures are formed that contain an outer membrane, an
abnormal inner membrane with poorly developed cristae,
Krebs cycle enzymes, and an incomplete respiratory chain
(6). These observations
are consistent with amino acid
incorporation
studies (3 1) that suggest that mitochondrial
DNA encodes for the synthesis ofhydrophobic
polypeptides
that are essential for complete assembly of functional inner
mitochondrial membranes.
As has been indicated above, the presence in cells of
altered mitochondrial
DNA results in the synthesis of
aberrant forms of mitochondrial
structures. What then is
the case in malignant cells, in many of which mitochondrial
DNA is different from normal? In malignant cells the
concentration
of mitochondrial
DNA is usually several
times greater than in normal cells, resembling the concen
tration found in embryonic cells (20). In mouse ascites cells,
in which many damaged mitochondria
appear, the mito
chondrial DNA has an abnormal topography (2 1). For a
recent review of mitochondrial DNA in malignant cells, see
Ref. 24.
Great interest has been shown in a unique unicircular
DNA dimer peculiar to mitochondria of human leukemic
leukocytes. The frequency of such molecules in cases of
chronic myelogenous leukemia was found to be proportion
ately related to the severity ofthe disease, while in remission
the dimer content declined (8). Dimers of this kind are not,
however, limited to human tumors (25) but are found also in
the normal human thyroid.
At present at least there is no evidencethat the informa
tion content of the abnormal dimer molecules of mitochon
drial DNA of human leukemic cells is different from that
of the normal monomer (24). Thus at present the connec
tion between abnormal mitochondrial DNA of human and
animal tumors and abnormal mitochondria is purely a cir
cumstantial one. Mitochondrial damage and abnormalities
of mitochondrial
DNA are common f'indings in malignant
cells. Mitochondrial mutagenesis, induced by intercalating
dyes such as ethidium bromide, produces forms that re
semble those seen in tumor cells. Changes in mitochondrial
structure and in the concentration
of mitochondrial cyto
chromes correlate with informational content of mitochon
drial cytochromes
correlate with informational
content
of mitochondrial DNA, and in vitro abnormal changes in
CANCER RESEARCH VOL. 35
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Mitochondria
mitochondrial
DNA are accompanied by changes in the
morphology and cytochrome content of mitochondria.
In the light of the role of mitochondrial genes in directing
the synthesis of key components of the mitochondrion,
numerous observations of tumor-associated
disturbances of
mitochondrial
function cannot be ignored. To quote an
outstanding authority in the field of cytoplasmic genetics:
“Inthe past only nuclear genes were taken into considera
tion in planning and evaluation of cancer research studies.
With the development of our knowledge about cytoplasmic
genetics, it would be useful to reconsider past studies and to
design new investigations aimed specifically at examining
the possible role of cytoplasmic genes in neoplastic transfor
mation― (27).
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NOVEMBER 1975
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3335
Is There a Role for Mitochondrial Genes in Carcinogenesis?
Henry D. Hoberman
Cancer Res 1975;35:3332-3335.
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