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• W2102371377 abstract "In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes taking place during net biomass formation and cell property maintenance. A crucial parameter for growth description is its yield, i.e. the efficiency of the transformation from substrate consumption to biomass formation. Using numerous yeast strains growing on different respiratory media, we have shown that the growth yield is identical regardless of the strain, growth phase, and respiratory substrate used. This homeostasis is the consequence of a strict linear relationship between growth and respiratory rates. Moreover, in all conditions tested, the oxygen consumption rate was strictly controlled by the cellular content of respiratory chain compounds in such a way that, in vivo, the steady state of oxidative phosphorylation was kept constant. Thus, the growth yield homeostasis depends on the tight adjustment of the cellular content of respiratory chain compounds to the growth rate. Any process leading to a defect in this adjustment allows an energy waste and consequently an energy yield decrease. In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes taking place during net biomass formation and cell property maintenance. A crucial parameter for growth description is its yield, i.e. the efficiency of the transformation from substrate consumption to biomass formation. Using numerous yeast strains growing on different respiratory media, we have shown that the growth yield is identical regardless of the strain, growth phase, and respiratory substrate used. This homeostasis is the consequence of a strict linear relationship between growth and respiratory rates. Moreover, in all conditions tested, the oxygen consumption rate was strictly controlled by the cellular content of respiratory chain compounds in such a way that, in vivo, the steady state of oxidative phosphorylation was kept constant. Thus, the growth yield homeostasis depends on the tight adjustment of the cellular content of respiratory chain compounds to the growth rate. Any process leading to a defect in this adjustment allows an energy waste and consequently an energy yield decrease. In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that can be assumed to take place during net biomass formation and maintenance processes (i.e. maintenance of ionic gradients, protein, lipid, and nucleic acid turnover) (1Westerhoff H.V. Hellingwerf K.J. van Dam K. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 305-309Crossref PubMed Scopus (127) Google Scholar, 2Gustafsson L. Thermochim. Acta. 1991; 193: 145-171Crossref Scopus (98) Google Scholar). During the last two decades, the complete thermodynamic description of growth processes has been obtained by establishing the balanced chemical reactions for anabolism and catabolism. A crucial parameter for growth evaluation is its yield, i.e. the efficiency of the transformation processes (from substrate consumption to biomass formation). The quantification of enthalpy efficiency (the energy converted into biomass divided by the energy input) has been successfully achieved for microorganisms (3Dermoun Z. Belaich J.P. J. Bacteriol. 1979; 140: 377-380Crossref PubMed Google Scholar, 4Dermoun Z. Belaich J.P. J. Bacteriol. 1980; 143: 742-746Crossref PubMed Google Scholar, 5Blomberg A. Larsson C. Gustafsson L. J. Bacteriol. 1988; 170: 4562-4568Crossref PubMed Google Scholar, 6Larsson C. Blomberg A. Gustafsson L. Biotechnol. Bioeng. 1991; 38: 447-458Crossref PubMed Scopus (50) Google Scholar) as well as for cultured mammalian cells (7Guan Y. Kemp R.B. Westerhoff H.V. Snoep J.L. Wijker J.E. Sluse F.E. Kholodenko B.N. Biothermokinetics of the Living Cell. Biothermokinetics Press, Amsterdam1996: 387-397Google Scholar, 8Kemp R.B. Evans P.M. Guan Y. Westerhoff H.V. Snoep J.L. Wijker J.E. Sluse F.E. Kholodenko B.N. Biothermokinetics of the Living Cell. Biothermokinetics Press, Amsterdam1996: 398-406Google Scholar). This approach is based on the continuous measurement of heat production and on the exhaustive determination of substrates and by-products, thus allowing the construction of enthalpy balances (see Refs. 2Gustafsson L. Thermochim. Acta. 1991; 193: 145-171Crossref Scopus (98) Google Scholar and 9von Stockar U. Gustafsson L. Larsson C. Marison I. Tissot P. Gnaiger E. Biochim. Biophys. Acta. 1993; 1183: 221-240Crossref Scopus (117) Google Scholar for reviews). Using this approach, we have previously shown (10Dejean L. Beauvoit B. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2000; 1457: 45-56Crossref PubMed Scopus (41) Google Scholar) that the enthalpic growth yield remains constant during any growth phase in yeast on respiratory substrate (i.e. exponential and transition phase). This constant enthalpic growth yield is owed to a tight adjustment of mitochondrial enzyme content to cellular energy demand (10Dejean L. Beauvoit B. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2000; 1457: 45-56Crossref PubMed Scopus (41) Google Scholar). This indicates that molecular mechanisms are involved in the growth yield homeostasis that allow a constant yield all throughout growth for a considered strain. However, when one is able to bypass the mitochondrial enzyme content adjustment, for example, through overactivation of the Ras/cAMP pathway, the growth yield is largely decreased (11Dejean L. Beauvoit B. Alonso A.P. Bunoust O. Guerin B. Rigoulet M. Biochim. Biophys. Acta. 2002; 1554: 159-169Crossref PubMed Scopus (32) Google Scholar). This led us to wonder whether any and every yeast strain has its own growth yield. In this paper, we have described a new and very simple method to assess the enthalpic growth yield through the amount of oxygen consumed to generate 1 mg of biomass, which allows the study of numerous strains. The main finding of this study is that the growth yield is identical regardless of the strain and growth phase, clearly pointing to a homeostasis process. We also show that the cellular respiratory rate is always strictly controlled by the respiratory chain content. Thus, the growth yield homeostasis is based on the tight adjustment of the cellular content of respiratory chain compounds to the growth rate. Any process leading to a defect in this adjustment allows an energy waste and consequently an energy yield decrease. Strains Used in This Study—The following strains were used: 1) W303–1A, Mata leu2–3, 112 ura3–1 trp1–1 his3–11, 15 ade2–1 can1–100 GAL SUC; 2) YSH652, Mata leu2–3, 112 ura3–1 trp1–1 his3–11, 15 ade2–1 can1–100 tps1::TRP1 tps2::LEU2 GAL SUC;3) YSH286, Mata leu2–3, 112 ura 3–52 trp1–92 GAL SUC; 4) YSH672, Mata leu2–3, 112 ura3–1 trp1–1 his3–11, 15 ade2–1 can1–100 tps2::LEU2 GAL SUC; 5) BY4742, MATaura3Δ0 lys2Δ0 leu2Δ0 his3Δ0(euroscarf); 6) Y11261, MATa his3Δ1 leu2Δ0 lys2Δ0 ura3Δ0 tpk1:: kanMX4(euroscarf); 7) Y11089, MATa his3Δ1 leu2Δ0 lys2Δ0 ura3Δ0 tpk2::kanMX4(euroscarf); 8) Y15016, MATa his3Δ1 leu2Δ0 lys2Δ0 ura3Δ0 tpk3::kanMX4(euroscarf); 9) OL556, a/a, cdc25–5/cdc25–5, his3/his3, leu2/leu2, rca1(pde2)/rca1, TRP1/trp1, ura3/ura3; 10) W303, a/a ade2–10/ade2–10 his3–11, 15/his3–11,15; leu2–3,112/leu2–3/112; 11) ura3–52/ura3–52; can1–100/can 1–100; trp1-Δ1/trp1-Δ1 + pYeDP-UCP1; 12) BD12–3B, a met-, ura3–8, ccs1–1; 13) SDC6, Mata leu2–3, 112 ura3–1 trp1–1 his3–11,15 ade2–1 can1–100 GAL SUC atp16::kanMX4 + pSDC13; and 14) yeast foam. Growth Media—The following growth media were used: (a) YPL 2% (1% yeast extract, 1% bactopeptone, 0.1% KH2PO4, 0.12% ammonium sulfate, 2% lactate, pH 5.5); (b) YPEG (1% yeast extract, 1% bactopeptone, 50 mm KH2PO4, 80 mg/ml adenine, 3% glycerol, 2% ethanol, pH 6.2); (c) SML 2% (0.17% yeast nitrogen base, without amino acids, without ammonium sulfate, 0.1% KH2PO4, 0.5% ammonium sulfate, 2% lactate, pH 5.5 (the concentration of auxotrophic requirements was 100 mg/liter)); (d) SML 0.2% (0.17% yeast nitrogen base, without amino acids, without ammonium sulfate, 0.1% KH2PO4, 0.5% ammonium sulfate, 0.2% lactate, pH 5.5 (the concentration of auxotrophic requirements was 100 mg/liter)); (e) SCL 2% (0.17% yeast nitrogen base, without amino acids, without ammonium sulfate, 0.1% KH2PO4, 0.5% ammonium sulfate, 2% lactate, pH 5.5, 1 g/liter casein hydrolysate (the concentration of auxotrophic requirements was 100 mg/liter)); and (f) SCL 0.2% (0.17% yeast nitrogen base, without amino acids, without ammonium sulfate, 0.1% KH2PO4, 0.5% ammonium sulfate, 0.2% lactate, pH 5.5, 1 g/liter casein hydrolysate (the concentration of auxotrophic requirements was 100 mg/liter)). Respiratory Rate Measurements—The oxygen consumption of cells was measured polarographically at 28 °C using a Clark oxygen electrode in a 1-ml thermostatically controlled chamber. Respiratory rates (JO2) were determined from the slope of a plot of O2 concentration versus time. Respiration assays of growing cells were performed in the growth medium, except in the case of the uncoupled respiration rate, which was performed after cells were harvested in the following buffer: 2 mm magnesium sulfate, 1.7 mm sodium chloride, 10 mm potassium phosphate, 10 mm glucose, and 100 mm ethanol, pH 6.8. Determination of Biomass over Oxygen Ratio—Growth was measured spectrophotometrically in different media by assessing the turbidity at 600 nm. Dry weight determinations were performed on samples of cells harvested throughout the growth period and washed twice in distilled water. For each strain, the relationship between dry weight and optical density was determined. The biomass over oxygen ratio (1/QO2) was the inverse of the integrated value of oxygen consumption by cells during the time necessary to increase the biomass of 1 mg dry weight. It was expressed as mg of dry weight/microatoms of oxygen. Cytochrome Content Determination—The cellular content of c + c1, b, and a + a3 hemes was calculated as described in Dejean et al. (10Dejean L. Beauvoit B. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2000; 1457: 45-56Crossref PubMed Scopus (41) Google Scholar), taking into account the respective molar extinction coefficient values and the reduced minus oxidized spectra recorded using a dual beam spectrophotometer (Aminco DW2000). Growth Yield Homeostasis—During the aerobic metabolism of mammalian cells, the calorimetric-respirometric ratio (i.e. CR ratio, defined as the ratio of heat production flux to oxygen consumption flux) has been proposed for assessing metabolic efficiency (12Clark D.G. Filsell O.H. Topping D.L. Biochem. J. 1979; 184: 501-507Crossref PubMed Scopus (45) Google Scholar, 13Jarrett I.G. Clark D.G. Filsell O.H. Harvey J.W. Clark M.G. Biochem. J. 1979; 180: 631-638Crossref PubMed Scopus (18) Google Scholar). A disproportional increase in heat production compared to oxygen uptake has been observed in isolated cells under conditions of enhanced futile substrate cycling (12Clark D.G. Filsell O.H. Topping D.L. Biochem. J. 1979; 184: 501-507Crossref PubMed Scopus (45) Google Scholar, 13Jarrett I.G. Clark D.G. Filsell O.H. Harvey J.W. Clark M.G. Biochem. J. 1979; 180: 631-638Crossref PubMed Scopus (18) Google Scholar) and uncoupling of oxidative phosphorylation (14Hoffner S.E. Meredith R.W. Kemp R.B. Cytobios. 1985; 42: 71-80PubMed Google Scholar). However, such high CR ratio values have been reinterpreted as a consequence of an increase in glycolysis under aerobic conditions rather than as a change in metabolic efficiency per se (15Kemp R.B. Gnaiger E. Wieser W. Gnaiger E. Energy Transformations in Cells and Organisms. Thieme Verlag, Stuttgart, Germany1989: 91-97Google Scholar, 16Gnaiger E. Kemp R.B. Biochim. Biophys. Acta. 1990; 1016: 328-332Crossref PubMed Scopus (154) Google Scholar). Although on-line calorimetry has been widely used to detect transitions in global metabolic activity during the growth of microorganisms (6Larsson C. Blomberg A. Gustafsson L. Biotechnol. Bioeng. 1991; 38: 447-458Crossref PubMed Scopus (50) Google Scholar, 17Samuelson M.O. Cadez P. Gustafsson L. Appl. Environ. Microbiol. 1988; 54: 2220-2225Crossref PubMed Google Scholar, 18von Stockar U. Birou B. Biotechnol. Bioeng. 1989; 34: 86-101Crossref PubMed Scopus (57) Google Scholar, 19van Urk H. Voll W. Scheffers W. van Dijken J.P. Yeast. 1988; 4: 283-391Crossref PubMed Scopus (130) Google Scholar, 20van Kleef B.H. Kuenen J.G. Heijnen J.J. Biotechnol. Prog. 1996; 12: 510-518Crossref PubMed Scopus (29) Google Scholar; and see Ref. 2Gustafsson L. Thermochim. Acta. 1991; 193: 145-171Crossref Scopus (98) Google Scholar for review), the relationships between oxygen consumption flux and heat production rate are poorly documented (but see Ref. 21Hoogerheide J.C. Radiat. Environ. Biophys. 1975; 12: 281-290Crossref PubMed Scopus (9) Google Scholar). We have previously developed a respirometric and calorimetric approach to determine the enthalpy efficiency of respiration-linked energy transformations of isolated yeast mitochondria and yeast cells under resting and growing conditions (22Dejean L. Beauvoit B. Bunoust O. Fleury C. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2001; 1503: 329-340Crossref PubMed Scopus (21) Google Scholar). In contrast to enthalpic balance approaches, this method does not rely on the exhaustive and tedious determination of the metabolites and elemental composition of biomass. Moreover, during the complete combustion of purely respiratory substrate such as lactate, each thermodynamic step corresponding to the consumption of one atom of oxygen corresponds to the same variation in enthalpy (21Hoogerheide J.C. Radiat. Environ. Biophys. 1975; 12: 281-290Crossref PubMed Scopus (9) Google Scholar). Because calorimetric-respirometric ratio assessment is a technique that requires heavy and rare equipment (microcalorimeter), we envisioned the possibility that the measure of both oxygen consumption and biomass would allow us to indirectly assess the enthalpic growth yield. When yeast cells are grown on a purely respiratory substrate, biomass generation is entirely connected to substrate oxidation through oxidative phosphorylation and, hence, to oxygen consumption. In a previous study, we have shown that either uncoupling or overactivation of the Ras/cAMP pathway leads to a decrease in the enthalpic growth yield through uncoupling between biomass synthesis and catabolism (10Dejean L. Beauvoit B. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2000; 1457: 45-56Crossref PubMed Scopus (41) Google Scholar, 11Dejean L. Beauvoit B. Alonso A.P. Bunoust O. Guerin B. Rigoulet M. Biochim. Biophys. Acta. 2002; 1554: 159-169Crossref PubMed Scopus (32) Google Scholar). These peculiar conditions gave us a broad range of enthalpic growth yields, which were connected to the biomass over oxygen ratio under the same experimental conditions. Fig. 1 clearly shows that there is a unique linear relationship between enthalpic growth yield and the biomass over oxygen ratio. This ratio is defined as the inverse of the amount of oxygen necessary to generate 1 mg dry weight of biomass. This validates our hypothesis, and by measuring both respiratory and growth rates, we have a good estimate of the growth yield. Moreover, this method, which has the advantages of being quick and simple, allowed us to investigate (i) whether the fact that enthalpic growth yield does not vary during growth is a general rule regardless of the yeast strain and the respiratory medium or (ii) whether the growth yield is a parameter that varies as a function of the yeast strain considered and/or the respiratory medium or a general feature that would be constant regardless of the strain. We measured the spontaneous respiratory rate as well as the growth rate of numerous yeast strains in different growth phases and in different respiratory media. Fig. 2 shows that there is a linear relationship between these two parameters on a broad range of values (respiratory rate varied from 60 to ∼350 nanoatoms of oxygen/min/mg dry weight). This shows that there is a tight adjustment between growth and respiratory rates, which is further confirmed by the fact that the growth yield expressed as the biomass over oxygen ratio remains almost constant. This shows that there is an actual homeostasis of growth yield in yeast. Loss of Growth Yield Homeostasis—However, from Fig. 1, one can see that, under peculiar conditions (uncoupling, overactivation of the Ras/cAMP cascade), the enthalpy growth yield is decreased, thus indicating that this homeostasis in growth yield can be lost. Obviously, when the coupling between respiratory chain and ATP synthase activities is altered, the growth yield must be affected by the increase in proton permeability of the inner mitochondrial membrane. This is clearly shown in Fig. 3; when uncoupling of oxidative phosphorylation is achieved either by means of UCP1 expression (22Dejean L. Beauvoit B. Bunoust O. Fleury C. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2001; 1503: 329-340Crossref PubMed Scopus (21) Google Scholar) or controlled depletion of the δ subunit of the ATP synthase (23Duvezin-Caubet S. Caron M. Giraud M.F. Velours J. di Rago J.P. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 13235-13240Crossref PubMed Scopus (45) Google Scholar), cells have a higher respiratory rate than control cells, which is not associated with a concomitant increase in growth rate. Consequently, there is a loss in growth yield homeostasis for these cells; the biomass over oxygen ratio is significantly decreased compared to wild type cells. Furthermore, previous work from our laboratory has shown that overactivation of the Ras/cAMP cascade induces a deregulation between the mitochondrial enzyme content and the growth rate (11Dejean L. Beauvoit B. Alonso A.P. Bunoust O. Guerin B. Rigoulet M. Biochim. Biophys. Acta. 2002; 1554: 159-169Crossref PubMed Scopus (32) Google Scholar, 24Dejean L. Beauvoit B. Bunoust O. Guerin B. Rigoulet M. Biochem. Biophys. Res. Commun. 2002; 293: 1383-1388Crossref PubMed Scopus (53) Google Scholar). Indeed, these mutants present an increase in the amount of mitochondrial enzyme content, which does not lead to a concomitant increase in growth rate. Depending on the kind of overactivation induced (Ras2Val19, cAMP addition), the increase in respiratory rate can be more or less important. This increase in respiratory rate from 180 to 340 nanoatoms of oxygen/min/mg dry weight does not lead to any increase in growth rate; thus, under these conditions, the relationship between respiratory rate and growth rate reaches a plateau (Fig. 3). Consequently, there is an exponential decrease in the biomass over oxygen ratio (see Fig. 3). It is noteworthy that whatever the means (uncoupling of oxidative phosphorylation or overactivation of the Ras/cAMP cascade) by which the tight adaptation between growth rate and respiratory rate is lost, there is the same relationship between either respiratory rate and growth rate or respiratory rate and biomass over oxygen ratio. This is indeed noteworthy, because the increase in respiratory rate has very different origins in the two situations: (i) UCP1 expression or controlled deletion of the ATP synthase δ subunit induces an increase in respiratory rate by inducing an increase in mitochondria inner membrane proton leak or (ii) in the case of the overactivation of the Ras/cAMP cascade, the increase in respiratory rate originates in an increase in the amount of mitochondrial enzymatic content. In this case, the mitochondria have been shown to be well differentiated and coupled (not shown) (see Ref. 11Dejean L. Beauvoit B. Alonso A.P. Bunoust O. Guerin B. Rigoulet M. Biochim. Biophys. Acta. 2002; 1554: 159-169Crossref PubMed Scopus (32) Google Scholar). Control of the Cellular Respiratory Rate—We then investigated the molecular basis of the homeostasis described above. Under conditions where yeast is grown on purely respiratory substrates, ATP synthesis mostly occurs within oxidative phosphorylation. A constant growth yield indicates that the part of ATP turnover involved in either biosynthesis or maintenance is constant. Yeast cell growth is characterized by two phases, an exponential one and the transition phase. We have shown that, during the last one, the decrease in growth rate is tightly linked to a decrease in mitochondrial enzyme content in such a way that the enthalpic growth yield is kept constant (10Dejean L. Beauvoit B. Guérin B. Rigoulet M. Biochim. Biophys. Acta. 2000; 1457: 45-56Crossref PubMed Scopus (41) Google Scholar). The question that is now raised is whether the fact that the growth yield is the same for any studied strain implicates that there is a tight adjustment between growth rate and the mitochondrial enzyme content. The amount of respiratory chains within a cell can be estimated through the cellular amount of mitochondrial cytochromes. We thus assessed the mitochondrial cytochrome content in the different strains under consideration, in different respiratory media and growth phases. If one plots the respiratory rate in these cells against the amount of each kind of cytochrome, one can clearly see that there is a linear relationship between these two parameters, indicating that respiratory rate in this case is mostly controlled by the amount of respiratory chain (Fig. 4). Because homeostasis is due to an adjustment between respiratory and growth rates, this implies that the mitochondrial enzyme content controls the growth rate. The question then arises as to understanding what controls the respiratory rate under conditions where the homeostasis is lost. We considered the loss of homeostasis due to overactivation of the Ras/cAMP pathway, because in this case, the oxidative phosphorylation remained well coupled. Fig. 4 shows that, in this case, the relationship between respiratory rate and cytochrome content is identical to the one obtained in the case of homeostasis. Therefore, cellular respiratory rate is always tightly controlled by cytochrome content. In this paper, we have unambiguously shown that the determination of the total amount of oxygen consumed to generate 1 mg of cell dry weight during growth on purely respiratory substrate allows an easy assessment of the growth yield. We have studied multiple strains and shown that the growth yield is maintained constant regardless of the strain considered, the growth phase, and of the respiratory substrate. In any wild type yeast strain, there is an actual homeostasis of growth yield, which is due to a tight adjustment of respiratory rate to the growth rate leading to a constant energy waste. Regardless of the pathway(s) allowing such an adjustment, it is clear that this process involves a good adjustment between the amount of cytochromes and the growth rate. In previous studies, Boumans et al. (25Boumans H. Berden J.A. Grivell L.A. J. Biol. Chem. 1998; 273: 4872-4877Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar) using a number of strains varying in steady state levels of assembled bc1 complex, have shown that there is a linear relationship between the level of bc1 complex and the respiratory rate of growing cells (see Ref. 26Boumans H. Berden J.A. Grivell L.A. van Dam K. Biochem. J. 1998; 331: 877-883Crossref PubMed Scopus (14) Google Scholar). Moreover, they observed that a reduced level of bc1 complex is associated with a parallel decrease in the steady state amount of cytochrome oxidase. They have proposed that the respiratory chain in yeast behaves as a single functional unit (24Dejean L. Beauvoit B. Bunoust O. Guerin B. Rigoulet M. Biochem. Biophys. Res. Commun. 2002; 293: 1383-1388Crossref PubMed Scopus (53) Google Scholar, 27Schägger H. Biochim. Biophys. Acta. 2002; 1555: 154-159Crossref PubMed Scopus (309) Google Scholar, 28Bunoust O. Devin A. Averet N. Camougrand N. Rigoulet M. J. Biol. Chem. 2005; 280: 3407-3413Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Indeed, Schägger has shown that Complexes III and IV are assembled into large supramolecular complexes. Along the same line but using another approach, we have shown that there is a very specific competition between electrons to enter the respiratory chain, which is also in favor of a supramolecular organization of the respiratory chain in which the relative ratio between any cytochrome remains constant (28Bunoust O. Devin A. Averet N. Camougrand N. Rigoulet M. J. Biol. Chem. 2005; 280: 3407-3413Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). This is in close agreement with the results presented in this paper, as we observed a parallel variation in all of the cytochromes for the different strains considered. It should be stressed that, for any of the cytochromes, there is a linear relationship between the cellular respiratory rate and the cytochrome amount crossing through the origin (see Fig. 4). This clearly indicates that the respiratory rate is fully controlled by each component of the respiratory chain. Such a fact indicates that there are respiratory chain units in which the electrons are channeled along the respiratory chain complexes. This is a strong argument in favor of a supramolecular organization of the mitochondrial respiratory chain in yeast, which is a hypothesis that clearly accounts for the full kinetic control of the oxygen consumption flux by each of the electron carriers. One of the pathways involved in the tight adjustment between the growth rate and the amount of cytochromes has been shown to be the Ras/cAMP pathway, which is involved in nutrient sensing. Whenever the activity of this pathway is increased, Ras2Val19 strain or OL556 strain in the presence of cAMP, the energy waste is increased because of the loss of adjustment of the respiratory rate to the growth rate in such a way that respiratory rate is increased, whereas growth rate remains constant. Indeed, in these mutants, the relationship between the amount of cytochromes and the respiratory rate is identical to the one obtained in various wild type strains (see Fig. 4). Consequently, the oxidative phosphorylation stationary state remains constant, i.e. the amount of oxygen consumed per minute and per unit of respiratory chain is constant. It is worth noting that there are physiological advantages for the cell to keep a constant stationary state in oxidative phosphorylation at ∼70% of the maximal rate of respiration observed in the presence of the uncoupler. Indeed, a higher respiratory rate requires a decrease in phosphate potential (i.e. the free energy in ATP synthesis), which would impair the cell functions, but lowering the respiratory rate leads to an increase in protonmotive force, which is well known to induce an increase in the mitochondrial generation of reactive oxygen species. Indeed this last situation has been observed when yeast cells enter the stationary phase and lead to a large enhancement of protein oxidation (29Aguilaniu H. Gustafsson L. Rigoulet M. Nystrom T. J. Biol. Chem. 2001; 276: 35396-35404Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). The fact that there is a unique relationship between respiratory rate and cytochrome content implies that respiratory rate and consequently ATP synthesis do not adjust to cellular energy demand. Indeed, in mutants overactivated in the Ras/cAMP pathway, both cytochrome content and respiratory rate increased, whereas the growth rate did not increase, leading to a decrease in growth yield, which implies an increase in energy waste. Consequently, the homeostasis in growth yield is due to the ability of cells to adapt the mitochondrial enzyme content to the growth rate. Even though the precise molecular mechanisms of this process are unknown to this day, it is clear that the Ras/cAMP pathway plays an important role in this regulation. We thank Dr. M. Jacquet for the OL556 strain, Prof. J. Thevelein for the YSH652, YSH286, and YSH672 strains, and Dr. J. P. Di Rago for the SDC6 strain." @default.
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• W2102371377 title "Growth Yield Homeostasis in Respiring Yeast Is Due to a Strict Mitochondrial Content Adjustment" @default.
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