The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) couple to oxygen consumption, 2) uncouple metabolism, 3) hydrolyze ATP, 4) control metabolic rate, 5) regulate metabolic rate, 6) produce heat, and 7) dissipate free energy. The quantitative contribution of different cellular reactions to these processes is assessed in mammals. We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis. The consequences of the significant contribution of proton leak to standard metabolic rate for tissue P-to-O ratio, heat production, and free energy dissipation by oxidative phosphorylation and the estimated contribution of ATP-consuming processes to tissue oxygen consumption rate are discussed. Of the 80% of oxygen consumption coupled to ATP synthesis, approximately 25-30% is used by protein synthesis, 19-28% by the Na(+)-K(+)-ATPase, 4-8% by the Ca2(+)-ATPase, 2-8% by the actinomyosin ATPase, 7-10% by gluconeogenesis, and 3% by ureagenesis, with mRNA synthesis and substrate cycling also making significant contributions. The main cellular reactions that uncouple standard energy metabolism are the Na+, K+, H+, and Ca2+ channels and leaks of cell membranes and protein breakdown. Cellular metabolic rate is controlled by a number of processes including metabolic demand and substrate supply. The differences in standard metabolic rate between animals of different body mass and phylogeny appear to be due to proportionate changes in the whole of energy metabolism. Heat is produced by some reactions and taken up by others but is mainly produced by the reactions of mitochondrial respiration, oxidative phosphorylation, and proton leak on the inner mitochondrial membrane. Free energy is dissipated by all cellular reactions, but the major contributions are by the ATP-utilizing reactions and the uncoupling reactions. The functions and evolutionary significance of standard metabolic rate are discussed.

Cellular energy utilization and molecular origin of standard metabolic rate in mammals

A role for ubiquitin in selective autophagy.

In early studies on energy metabolism of tumor cells, it was proposed that the enhanced glycolysis was induced by a decreased oxidative phosphorylation. Since then it has been indiscriminately applied to all types of tumor cells that the ATP supply is mainly or only provided by glycolysis, without an appropriate experimental evaluation. In this review, the different genetic and biochemical mechanisms by which tumor cells achieve an enhanced glycolytic flux are analyzed. Furthermore, the proposed mechanisms that arguably lead to a decreased oxidative phosphorylation in tumor cells are discussed. As the O(2) concentration in hypoxic regions of tumors seems not to be limiting for the functioning of oxidative phosphorylation, this pathway is re-evaluated regarding oxidizable substrate utilization and its contribution to ATP supply versus glycolysis. In the tumor cell lines where the oxidative metabolism prevails over the glycolytic metabolism for ATP supply, the flux control distribution of both pathways is described. The effect of glycolytic and mitochondrial drugs on tumor energy metabolism and cellular proliferation is described and discussed. Similarly, the energy metabolic changes associated with inherent and acquired resistance to radiotherapy and chemotherapy of tumor cells, and those determined by positron emission tomography, are revised. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2007.05686.x

Energy metabolism in tumor cells

Proteins presented to the immune system must first be cleaved to small peptides by intracellular proteinases. Proteasomes are proteolytic complexes that degrade cytosolic and nuclear proteins. These particles have been implicated in ATP-ubiquitin-dependent proteolysis and in the processing of intracellular antigens for cytolytic immune responses.

Proteolysis, proteasomes and antigen presentation

Cancer metabolism: facts, fantasy, and fiction.

The report deals with a detailed balance of ATP production and consumption of the rabbit reticulocyte.



1. The sum-total of ATP produced amounts to 135mmol · l−1· h−1.



2. About 70% of the ATP consumption has been accounted for by specific processes. The main contributing processes are the globin synthesis with about 28%, the Na+, K+-ATPase with 23% and the proteolysis with more than 15%. 30% of ATP consumption has not been accounted for.



3. Cycloheximide (20 μM) leads to a dissociation between synthesis and degradation of proteins, which argues against any obligatory connection between these processes.



4. More than 90% of the lysine liberated from mitochondria by proteolysis were reutilized for the globin synthesis demonstrating the high nitrogen economy of reticulocytes.



5. Each of the ATP-consuming processes studied appears to control ATP production in an independent manner without competition with each other.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1984.tb07982.x

Accounting for the ATP-consuming processes in rabbit reticulocytes

ATP production of Ehrlich ascites tumour cells was estimated on the basis of their coupled respiration and lactate formation. ATP-consuming processes were assessed from the effects of selective inhibitors of RNA synthesis, protein synthesis and proteolysis, Na+/K+-ATPase on respiration. The extent of protein synthesis and proteolysis were also determined directly. From these values and those of the inhibition of respiration by selective inhibitors, a P/O ratio of 2.2 was calculated. About 75% of the total ATP consumption could be assigned to specific processes. The major ATP-consuming processes of tumour cells in an amino-acid-enriched medium, in which they are in an approximate steady state, are protein synthesis with about 30% of total ATP consumption, and Na+/K+-ATPase with about 20%, while RNA synthesis, ATP-dependent proteolysis and Ca2+-ATPase contribute about 10% each. In an amino-acid-free glucose medium, protein synthesis is reduced to a third, with a corresponding decrease of respiration, whereas the rate of the other ATP-consuming processes is unchanged.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1986.tb10496.x

Quantification of ATP-producing and consuming processes of Ehrlich ascites tumour cells.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2885%2981080-2

Proteolysis of mitochondria in reticulocytes during maturation is ubiquitin-dependent and is accompanied by a high rate of ATP hydrolysis

A method is reported, based on the isotopic dilution of lysme, which is suitable for the measurement of the degradation of stroma proteins of reticulocytes. 2. Proteolysis is extensive and time-limited. It may reach 50% of the stroma in 2 h at pH 7.6 and 37°C. It is strongly dependent on pH and temperature, being small at low pH and temperatures. Proteolysis is largely ATP-dependent. The extent of proteolysis is nearly proportional to the degree of reticulocytosis. 3. The proteolytic system may be reconstructed in hemolysates if ATP is produced or supplied. It is assumed that the system is identical with that studied by Goldberg et al. and Hershko et al. on abnormal or denatured proteins as substrates. The main significance of the proteolytic system appears to be the degradation of mitochondria during maturation of the red cell. Energy-dependent proteolysis has since its dis- covery [l

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1980.tb04808.x

Determination and Characteristics of Energy‐Dependent Proteolysis in Rabbit Reticulocytes

In reticulocytes exists an extensive and time-limited ATP-dependent proteolysis which has been measured by a new method. This enzyme system attacks exclusively the mitochondria during the maturation of reticulocytes. The proteolysis is inhibited by anaerobiosis and salicylhydroxamic acid which indicates that it is preceded by the attack of lipoxygenase. There is some evidence for the universality of the ATP-dependent proteolysis, since liver mitochondria are also subject to it.

Müller M

Papers

Accounting for the ATP-consuming processes in rabbit reticulocytes

Quantification of ATP-producing and consuming processes of Ehrlich ascites tumour cells.

Proteolysis of mitochondria in reticulocytes during maturation is ubiquitin-dependent and is accompanied by a high rate of ATP hydrolysis

Determination and Characteristics of Energy‐Dependent Proteolysis in Rabbit Reticulocytes

Determination and characteristics of energy-dependent proteolysis in rabbit reticulocytes.