Mitochondrial Physiology Network 10.9: 73 (2005) - download pdf

Mitochondria are sensitive to carcinogenic chemicals.

Valgardur Egilsson

University Hospital of Iceland, Reykjavik, Iceland. - valgarde@landspitali.is

    Background  It is well known that under fast proliferation cells tend to use high glycolysis and low respiration. Examples of this are embryonic cells (of low differentiation) and cells in vitro. Fast proliferating cells prefer glucose, although non-fermentable (respiration dependent) substrates are available too. Cancer cells show strikingly high glycolysis while their respiration is low or disturbed (1). Cancer cells are generally of low stage differentiation. Cells of high degree differention usually show high respiration.

    The associations above lead to a question: is there a causal relationship between e. g. the degree of differentiation and  respiration? Or between proliferation rate and rate of glycolysis? In embryonic cells the glycolysis / respiration  ratio  undoubtedly is regulated, by some normal physiological mechanism (i.e. it is not caused by “lack of oxygen “ as may be in some cases of cancer).

    We found that mitochondria dependent functions were relatively sensitive to toxic effects of various carcinogenic  chemicals (2). We assessed the growth inhibitory effects of the chemicals on the yeast Saccharomyces cerevisiae plated on fermentable versus  non-fermentable medium (glucose versus glycerol as the sole carbon source). On non-fermentable  (respiratory) medium, concentrations of carcinogens inhibiting growth were much lower than on fermentable medium.The difference was upto ten-fold. Among the carcinogens tested were thioacetamide, 4-nitroquinoline-N-oxide, adriamycine , ethionine, thiourea, 2-naphthylamine, benzidine and cadmium. At the same time mitochondrial DNA frequently showed  petite mutations.

    Experiments on the regulation of the respiration /glycolysis ratio showed that petite mutants may be incapable of utilizing  galactose to support growth although the wild type parent strain grows on that substrate; this mitochondrial sugar utilization factor needs a renewed interest.

    One also noticed how well petite  strains grow on glucose medium. In shaking culture (wild type strain) the cell mass (biomass) obtained from high glucose medium (under glucose repression (catabolite repression) was compared to the cell mass obtained from growth under non-fermentable conditions (with glycerol as the sole carbon source). The amount of carbon source used was measured, i.e. the diminishing of the carbon source in the medium. In other words, for a given biomass (amount) obtained under these two different growth conditions  the amount of substrate was known.

    It is of interest to compare the calculated amount of ATP theoretically obtainable from the amount of substrate used. In case of the respiratory culture, this calculated figure was 2.5 – 3.0 times higher than for culture under glucose repressed condition. This leads to the next question: could the cell cycle be more expensive energy-wise when the mitochondria are at work and the cell cycle is much longer?

1.    Warburg O (1931) The metabolism of tumors. New York: RR Smith.

2.  Egilsson V, Evans IH, Wilkie D (1978) Toxic and muagenic effects of carcinogens on the mitochondria of Saccharomyces cerevisae. Mol. Gen. Genet. 174: 39-46.