- Email: [email protected]
Mitochondrial regulation of cell surface components in relation to carcinogenesis
J. theor. Biol. (1984) 110, 377-381
Mitochondrial Regulation of Cell Surface Components in Relation to Carcinogenesis PHILIP JOHN
Department of Agricultural Botany, Plant Science Laboratories, University of Reading, Whiteknights, Reading RG6 2AS, England (Received 28 January 1984, and in revised form 1 March 1984) The recently discovered mitochondriai regulation of certain surface properties of yeast and mouse cells is explained in terms of the intragenomic conflict and interallelic competition that can arise within an organism from the cytoplasmic inheritance of mitochondrial genes. These considerations lend support to the view that an alteration of mitochondrial DNA is one of the steps in chemical carcinogenesis.
Introduction It has recently become apparent that mitochondria can exert a controlling influence over certain cell surface properties. In yeast (Saccharomyces cerevisiae) Wilkie et al. (1983) have shown that damage to the mitochondrial genome results not only in a defective respiratory system but also in the inability of cells to take up certain sugars such as galactose and maltose, in a loss of flocculence, in an enhanced sensitivity to agglutination by concanavalin A, and in altered cell surface properties as revealed by a changed partitioning o f cells in an aqueous biphasic system of polyethylene glycol and dextran. The types of cell surface changes observed in yeast are characteristic of those that accompany the neoplastic transformation of mammalian cells that have been treated with chemical carcinogens. Moreover, in yeast the mitochondria are the primary target for a variety of chemicals known to be carcinogenic in mammals (Egilsson, Evans & Wilkie, 1979). These findings are consistent with evidence obtained with mammalian oells which has indicated that susceptibility to carcinogens is much greater.for the naked D N A o f the mitochondria than for the relatively protected D N A of the nucleus (Wiinderlich et al., 1970; Allen & Coombs, 1980; Backer & Weinstein, 1980). Thus it has been argued that while the nucleus may well be the target for oncogenic viruses, genetic damage to mitochondrial D N A is the first step in at least some cases o f chemical carcinogenesis (Wilkie et al., 1983). 377 0022-5193/84/190377+05
$03.00/0
© 1984 Academic Press Inc. (London) Ltd.
378
P. J O H N
The relevance of this work with yeast to the development of cancer in mammalian systems has recently been strengthened by the discovery that expression of a cell surface antigen in the mouse requires functionally complete mitochondria. The evidence obtained both from selective crosses (Lindahl, Hausmann & Chapman, 1983) and from somatic cell hybridization (Smith et al., 1983) has been interpreted to indicate that expression of a maternally-transmitted, antigenic glycoprotein at the cell surface is likely to be controlled by a product of mitochondrial genes, while the structural gene, probably a member of the major histo-compatibility complex, is nuclear. In the absence of any obvious functional link between mitochondria and the cell membrane, an explanation for a mitochondrial control over the cell surface has not been readily available. The present paper attempts to remedy this deficiency by showing that a control by mitochondrial genes over the expression of nuclear genes may be explained in terms of the intragenomic conflicts and interaUelic competition that can arise within an organism from the cytoplasmic inheritance of mitochondrial genes.
lntragenomic Conflict The interaction of mitochondrial and nuclear genes has been viewed primarily as a cooperative effort directed towards the reproductive success of the eukaryotic cell as a whole (Margulis, 1981). Where, as is generally the case, the interests of mitochondrial and nuclear genes coincide, for example in cellular development and metabolism, then the two categories of genes can be considered to be coadapted components, acting together to increase the fitness of the whole organism. However, coadaptiveness is an inadequate concept when sexual reproduction and somatic cell division are considered, because of the different patterns of inheritance of mitochondrial and nuclear genes (Eherhard, 1980; Cosmides & Tooby, 1981). Both in the allocation of genetic material to the gametes and in somatic cell division, mitochondrial genes are transmitted independently of the nuclear genes. Consequently, circumstances that are selectively advantageous for one set of genes may be selectively disadvantageous to the other set. Thus conflict can arise within the genome of the organism between the coreplicating set of nuclear genes on the one hand, and the independently coreplicating set of mitochondrial genes on the other. Although "the idea of intraorganismal conflict runs counter to the common conceptions that nucleus-organelle interactions are entirely symbiotic" (Eberhard, 1980) it should be emphasised that the concept of intraorganismal conflict is independent of whether mitochondria originated as endosymbionts--as seems likely (John & Whatley, 1975; Gray & Doolittle,
MITOCHONDRIA AND THE CELL SURFACE
379
1982)--or in some other way. Conflict or cooperation between mitochondrial and nuclear genes in present-day organisms does not depend on the historical origins of the mitochondria. Rather it depends on whether the genes stand to gain or lose by the way in which they interact. The number of mitochondrial genes in animal and plant cells is very much smaller than the number of nuclear genes, and the influence of mitochondrial genes on the phenotype must be correspondingly more limited. However, if a few mitochondrial genes acted to modify the action of nuclear genes their influence on the phenotype would be out of all proportion to their number. For these reasons Cosmides & Tooby (1981) suggested that "cytoplasmic genes may on occasion be regulatory genes for nuclear material". This suggestion has now been substantiated by the finding that lesions in the mitochondrial DNA lead to modulation of the activity of certain nuclear genes involved in cell surface biogenesis in yeast (Wilkie et al., 1983), and that mitochondrial DNA may well be involved in the expression of a cell surface antigen in the mouse (Lindahl et ai., 1983; Smith et al., 1983). Hence the otherwise unexpected link between mitochondrial function and the properties of the cell membrane is consistent with, and predicted by, analyses of the intragenomic conflict which results from the cytoplasmic inheritance of mitochondrial genes. lnterallelic Competition When an embryonic cell differentiates into a somatic cell its reproductive potential is sacrificed so as to enhance the ultimate propagation of the genes resident in the gametes. In an animal mitosis ensures that all cells, including the gametocytes, contain at least one copy of the entire nuclear genome. Thus the propagation of the nuclear genes is enhanced by the nonreproductive activities of the somatic cells, the growth and multiplication of which are constrained by the morphological and physiological requirements of the whole organism. By comparison with the ordered replication and transmission of nuclear genes during mitotic cell division, the distribution of mitochondrial genes during mitotic cell division appears to be less controlled. The salient features are as follows (for review see Birky, 1978; Gillham, 1978). First, within each animal cell there are a large and variable number of copies of the mitochondrial genome packaged in a variable number of mitochondria. Secondly, despite the large number of physical copies within a cell, there seem to be few genetic copies (Gillham, 1978), and mutations of mitochondrial DNA are readily detected by their effect on the phenotype. This intracellular selection of mutant alleles in a multicopy system can be explained for the petite mutation in yeast, where the presence of certain nucleotide sequences and other features of the defective genome
380
P. JOHN
endow it with a replicative advantage over the wild type genome, the expression of which can become suppressed (Bernardi, 1982). Thirdly, while alleles of nuclear genes segregate only at meiosis, mitochondrial genes can "segregate" during mitotic divisions of the eukaryotic cell. This vegetative segregation permits an initially heteroplasmic cell to give rise to homoplasmic daughter cells during somatic cell divisions. Thus during the somatic growth of an animal, while the identity of the nuclear genes is generally conserved by mitosis, the relatedness of mitochondrial genes may be reduced by mutation, selection and vegetative segregation. Consequently different parts of the same organism, identical with respect to their nuclear genes, could come to have a low relatedness with respect to their mitochondrial genes (Cosmides & Tooby, 1981 ). This intraorganismal differentiation would lead to competition between different parts of the organism for resources, even though in a vertebrate transmission of the successful mitochondrial genes to the next generation would occur only in the extremely unlikely event that they replaced competing mitochondrial genes early enough in embryogenesis to be included in the female gametocyte (Eberhard, 1980; Cosmides & Tooby, 1981). Usually then, all contestants in this interallelic competition would lose, since the organism as a whole would suffer from the resulting loss of organismal integrity. Because of the potential for this kind of struggle, there would be a selective advantage to be gained by any particular mitochondrial genome if its cell cooperated only with other cells that contained a copy of the same mitochondrial genome. This would require intercellular recognition which could be achieved most simply by a mitochondrial modulation of those nuclear genes which specify cell surface features. The selective advantage conferred on the nuclear genes by a cooperation with this arrangement would be that it helped to avoid an intraorganismal conflict which, whatever the outcome, would be deleterious to the reproduction of the nuclear genes. It has already been recognised that nuclear genes act to minimize conflict between competing mitochondrial alleles within the cell, by the creation of homoplasmia through the destruction of minority alleles (Cosmides & Tooby, 1981). It is proposed here that the newly-discovered mitochondrial determination of cell surface components (Wilkie et al., 1983; Lindahl et al., 1983; Smith et al., 1983) helps to minimize conflicts between competing mitochondrial genes present in different cells.
Carcinogenesis The implications of the foregoing considerations for carcinogenesis are as follows. When mitochondrial DNA is altered by attack from certain
MITOCHONDRIA
AND THE CELL SURFACE
381
chemical carcinogens, the alteration in the mitochondrial genome is reflected in changes at the cell surface so that the altered cell becomes morphogenically isolated from the neighbouring cells. Subsequent development of the rejected cell would depend upon nuclear events. Undamaged nuclei would presumably restrict the development of cells dominated by minority mitochondrial alleles, and the cell would remain quiescent. When an appropriate nuclear background is provided by the intervention of an oncogenic virus, by the activation of an oncogene or by other carcinogenic means, then the result would be an unrestricted series of cell growth and division leading to neoplasia. Within the neoplasm there are "'subpopulations of cancer cells that coexist and interact in the heterogenous tumor tissue to insure the continued development and survival of the malignancy" (Dexter & Calabresi, 1982). Thus the diverse descendants of the mutant cell collaborate with one another to enhance their own survival, while they compete with the normal cells for the available resources of the organism. The only selective advantage possessed by the cancer cells is, presumably, their failure to obey the normal restrictions on cell division and growth. The selective disadvantage possessed by the cancer cells might well be, at least in some cases, the presence of defective mitochondria. These represent a potential weakness which would make treatment with antimitochondrial drugs an effective form of chemotherapy for at least some kinds of cancer (Wilkie, 1979). REFERENCES ALLEN, J. A. & COOMBS, M. M. (1980). Nature, Lond. 287, 244. BACKER, J. M. g/. WEINSTEIN, I. B. (1980). Science, 209, 297. BERNARDI, G. (I982). Trends Biochem. Sci. 7, 404. BIRKY, C. W. (1978). A. Rev. Genet. 12, 471. COSM1DES, L. H. & TOOBY, J. (1981). J. theor. Biol. 89, 83. DEXTER, D. L. & CALABRESl, P. (1982). Biochim. biophys. Acta 695, 97. EaERHARD, W. G. (1980). Q. Rev. Biol. 55, 231. EGILSSON, V., EVANS, I. H. ~¢. WILKIE, D. (1979). Molec. Gen. Genet. 174, 39. GILLHAM, N. W. (1978). Organelle Heredity. New York: Raven Press. GRAY, M. W. g/. DOOLITTLE, W. F. (1982). Microbiol. Rev. 46, I. JOHN, P. • WHATLEY, F. R. (1975). Nature, Lond. 254, 495. LINDAHL, K. F., HAUSMANN, B. & CHAPMAN, V. M. (1983). Nature, Lond. 306, 383. MARGULIS, L. (1981). Symbiosis In Cell Evolution. San Francisco: W. H. Freeman. SMITH, R. II1, HUSTON, M. M., JENKINS, R. N., HUSTON, D. P. & RICH, R. R. (1983). Nature, Lond. 306, 599. WlLKIE, D. (1979). Jl R. Soc. Med. 72, 599. WlLKIE, D., EVANS, I. H., EG1LSSON, V., DIALA, E. S. & COLLIER, D. (1983). Int. Rev. Cytol. Supp. 15, 157. W0NDERLICH, V., SCHOTr, M., B6TTGER, M. & GRAFFI, A. (1979). Biochem. J. 118, 99.
Mitochondrial Regulation of Cell Surface Components in Relation to Carcinogenesis PHILIP JOHN
Department of Agricultural Botany, Plant Science Laboratories, University of Reading, Whiteknights, Reading RG6 2AS, England (Received 28 January 1984, and in revised form 1 March 1984) The recently discovered mitochondriai regulation of certain surface properties of yeast and mouse cells is explained in terms of the intragenomic conflict and interallelic competition that can arise within an organism from the cytoplasmic inheritance of mitochondrial genes. These considerations lend support to the view that an alteration of mitochondrial DNA is one of the steps in chemical carcinogenesis.
Introduction It has recently become apparent that mitochondria can exert a controlling influence over certain cell surface properties. In yeast (Saccharomyces cerevisiae) Wilkie et al. (1983) have shown that damage to the mitochondrial genome results not only in a defective respiratory system but also in the inability of cells to take up certain sugars such as galactose and maltose, in a loss of flocculence, in an enhanced sensitivity to agglutination by concanavalin A, and in altered cell surface properties as revealed by a changed partitioning o f cells in an aqueous biphasic system of polyethylene glycol and dextran. The types of cell surface changes observed in yeast are characteristic of those that accompany the neoplastic transformation of mammalian cells that have been treated with chemical carcinogens. Moreover, in yeast the mitochondria are the primary target for a variety of chemicals known to be carcinogenic in mammals (Egilsson, Evans & Wilkie, 1979). These findings are consistent with evidence obtained with mammalian oells which has indicated that susceptibility to carcinogens is much greater.for the naked D N A o f the mitochondria than for the relatively protected D N A of the nucleus (Wiinderlich et al., 1970; Allen & Coombs, 1980; Backer & Weinstein, 1980). Thus it has been argued that while the nucleus may well be the target for oncogenic viruses, genetic damage to mitochondrial D N A is the first step in at least some cases o f chemical carcinogenesis (Wilkie et al., 1983). 377 0022-5193/84/190377+05
$03.00/0
© 1984 Academic Press Inc. (London) Ltd.
378
P. J O H N
The relevance of this work with yeast to the development of cancer in mammalian systems has recently been strengthened by the discovery that expression of a cell surface antigen in the mouse requires functionally complete mitochondria. The evidence obtained both from selective crosses (Lindahl, Hausmann & Chapman, 1983) and from somatic cell hybridization (Smith et al., 1983) has been interpreted to indicate that expression of a maternally-transmitted, antigenic glycoprotein at the cell surface is likely to be controlled by a product of mitochondrial genes, while the structural gene, probably a member of the major histo-compatibility complex, is nuclear. In the absence of any obvious functional link between mitochondria and the cell membrane, an explanation for a mitochondrial control over the cell surface has not been readily available. The present paper attempts to remedy this deficiency by showing that a control by mitochondrial genes over the expression of nuclear genes may be explained in terms of the intragenomic conflicts and interaUelic competition that can arise within an organism from the cytoplasmic inheritance of mitochondrial genes.
lntragenomic Conflict The interaction of mitochondrial and nuclear genes has been viewed primarily as a cooperative effort directed towards the reproductive success of the eukaryotic cell as a whole (Margulis, 1981). Where, as is generally the case, the interests of mitochondrial and nuclear genes coincide, for example in cellular development and metabolism, then the two categories of genes can be considered to be coadapted components, acting together to increase the fitness of the whole organism. However, coadaptiveness is an inadequate concept when sexual reproduction and somatic cell division are considered, because of the different patterns of inheritance of mitochondrial and nuclear genes (Eherhard, 1980; Cosmides & Tooby, 1981). Both in the allocation of genetic material to the gametes and in somatic cell division, mitochondrial genes are transmitted independently of the nuclear genes. Consequently, circumstances that are selectively advantageous for one set of genes may be selectively disadvantageous to the other set. Thus conflict can arise within the genome of the organism between the coreplicating set of nuclear genes on the one hand, and the independently coreplicating set of mitochondrial genes on the other. Although "the idea of intraorganismal conflict runs counter to the common conceptions that nucleus-organelle interactions are entirely symbiotic" (Eberhard, 1980) it should be emphasised that the concept of intraorganismal conflict is independent of whether mitochondria originated as endosymbionts--as seems likely (John & Whatley, 1975; Gray & Doolittle,
MITOCHONDRIA AND THE CELL SURFACE
379
1982)--or in some other way. Conflict or cooperation between mitochondrial and nuclear genes in present-day organisms does not depend on the historical origins of the mitochondria. Rather it depends on whether the genes stand to gain or lose by the way in which they interact. The number of mitochondrial genes in animal and plant cells is very much smaller than the number of nuclear genes, and the influence of mitochondrial genes on the phenotype must be correspondingly more limited. However, if a few mitochondrial genes acted to modify the action of nuclear genes their influence on the phenotype would be out of all proportion to their number. For these reasons Cosmides & Tooby (1981) suggested that "cytoplasmic genes may on occasion be regulatory genes for nuclear material". This suggestion has now been substantiated by the finding that lesions in the mitochondrial DNA lead to modulation of the activity of certain nuclear genes involved in cell surface biogenesis in yeast (Wilkie et al., 1983), and that mitochondrial DNA may well be involved in the expression of a cell surface antigen in the mouse (Lindahl et ai., 1983; Smith et al., 1983). Hence the otherwise unexpected link between mitochondrial function and the properties of the cell membrane is consistent with, and predicted by, analyses of the intragenomic conflict which results from the cytoplasmic inheritance of mitochondrial genes. lnterallelic Competition When an embryonic cell differentiates into a somatic cell its reproductive potential is sacrificed so as to enhance the ultimate propagation of the genes resident in the gametes. In an animal mitosis ensures that all cells, including the gametocytes, contain at least one copy of the entire nuclear genome. Thus the propagation of the nuclear genes is enhanced by the nonreproductive activities of the somatic cells, the growth and multiplication of which are constrained by the morphological and physiological requirements of the whole organism. By comparison with the ordered replication and transmission of nuclear genes during mitotic cell division, the distribution of mitochondrial genes during mitotic cell division appears to be less controlled. The salient features are as follows (for review see Birky, 1978; Gillham, 1978). First, within each animal cell there are a large and variable number of copies of the mitochondrial genome packaged in a variable number of mitochondria. Secondly, despite the large number of physical copies within a cell, there seem to be few genetic copies (Gillham, 1978), and mutations of mitochondrial DNA are readily detected by their effect on the phenotype. This intracellular selection of mutant alleles in a multicopy system can be explained for the petite mutation in yeast, where the presence of certain nucleotide sequences and other features of the defective genome
380
P. JOHN
endow it with a replicative advantage over the wild type genome, the expression of which can become suppressed (Bernardi, 1982). Thirdly, while alleles of nuclear genes segregate only at meiosis, mitochondrial genes can "segregate" during mitotic divisions of the eukaryotic cell. This vegetative segregation permits an initially heteroplasmic cell to give rise to homoplasmic daughter cells during somatic cell divisions. Thus during the somatic growth of an animal, while the identity of the nuclear genes is generally conserved by mitosis, the relatedness of mitochondrial genes may be reduced by mutation, selection and vegetative segregation. Consequently different parts of the same organism, identical with respect to their nuclear genes, could come to have a low relatedness with respect to their mitochondrial genes (Cosmides & Tooby, 1981 ). This intraorganismal differentiation would lead to competition between different parts of the organism for resources, even though in a vertebrate transmission of the successful mitochondrial genes to the next generation would occur only in the extremely unlikely event that they replaced competing mitochondrial genes early enough in embryogenesis to be included in the female gametocyte (Eberhard, 1980; Cosmides & Tooby, 1981). Usually then, all contestants in this interallelic competition would lose, since the organism as a whole would suffer from the resulting loss of organismal integrity. Because of the potential for this kind of struggle, there would be a selective advantage to be gained by any particular mitochondrial genome if its cell cooperated only with other cells that contained a copy of the same mitochondrial genome. This would require intercellular recognition which could be achieved most simply by a mitochondrial modulation of those nuclear genes which specify cell surface features. The selective advantage conferred on the nuclear genes by a cooperation with this arrangement would be that it helped to avoid an intraorganismal conflict which, whatever the outcome, would be deleterious to the reproduction of the nuclear genes. It has already been recognised that nuclear genes act to minimize conflict between competing mitochondrial alleles within the cell, by the creation of homoplasmia through the destruction of minority alleles (Cosmides & Tooby, 1981). It is proposed here that the newly-discovered mitochondrial determination of cell surface components (Wilkie et al., 1983; Lindahl et al., 1983; Smith et al., 1983) helps to minimize conflicts between competing mitochondrial genes present in different cells.
Carcinogenesis The implications of the foregoing considerations for carcinogenesis are as follows. When mitochondrial DNA is altered by attack from certain
MITOCHONDRIA
AND THE CELL SURFACE
381
chemical carcinogens, the alteration in the mitochondrial genome is reflected in changes at the cell surface so that the altered cell becomes morphogenically isolated from the neighbouring cells. Subsequent development of the rejected cell would depend upon nuclear events. Undamaged nuclei would presumably restrict the development of cells dominated by minority mitochondrial alleles, and the cell would remain quiescent. When an appropriate nuclear background is provided by the intervention of an oncogenic virus, by the activation of an oncogene or by other carcinogenic means, then the result would be an unrestricted series of cell growth and division leading to neoplasia. Within the neoplasm there are "'subpopulations of cancer cells that coexist and interact in the heterogenous tumor tissue to insure the continued development and survival of the malignancy" (Dexter & Calabresi, 1982). Thus the diverse descendants of the mutant cell collaborate with one another to enhance their own survival, while they compete with the normal cells for the available resources of the organism. The only selective advantage possessed by the cancer cells is, presumably, their failure to obey the normal restrictions on cell division and growth. The selective disadvantage possessed by the cancer cells might well be, at least in some cases, the presence of defective mitochondria. These represent a potential weakness which would make treatment with antimitochondrial drugs an effective form of chemotherapy for at least some kinds of cancer (Wilkie, 1979). REFERENCES ALLEN, J. A. & COOMBS, M. M. (1980). Nature, Lond. 287, 244. BACKER, J. M. g/. WEINSTEIN, I. B. (1980). Science, 209, 297. BERNARDI, G. (I982). Trends Biochem. Sci. 7, 404. BIRKY, C. W. (1978). A. Rev. Genet. 12, 471. COSM1DES, L. H. & TOOBY, J. (1981). J. theor. Biol. 89, 83. DEXTER, D. L. & CALABRESl, P. (1982). Biochim. biophys. Acta 695, 97. EaERHARD, W. G. (1980). Q. Rev. Biol. 55, 231. EGILSSON, V., EVANS, I. H. ~¢. WILKIE, D. (1979). Molec. Gen. Genet. 174, 39. GILLHAM, N. W. (1978). Organelle Heredity. New York: Raven Press. GRAY, M. W. g/. DOOLITTLE, W. F. (1982). Microbiol. Rev. 46, I. JOHN, P. • WHATLEY, F. R. (1975). Nature, Lond. 254, 495. LINDAHL, K. F., HAUSMANN, B. & CHAPMAN, V. M. (1983). Nature, Lond. 306, 383. MARGULIS, L. (1981). Symbiosis In Cell Evolution. San Francisco: W. H. Freeman. SMITH, R. II1, HUSTON, M. M., JENKINS, R. N., HUSTON, D. P. & RICH, R. R. (1983). Nature, Lond. 306, 599. WlLKIE, D. (1979). Jl R. Soc. Med. 72, 599. WlLKIE, D., EVANS, I. H., EG1LSSON, V., DIALA, E. S. & COLLIER, D. (1983). Int. Rev. Cytol. Supp. 15, 157. W0NDERLICH, V., SCHOTr, M., B6TTGER, M. & GRAFFI, A. (1979). Biochem. J. 118, 99.