Cell cycle progression is regulated by intertwined redox oscillators.

Jorgelindo Da Veiga Moreira,Jean-Marc Steyaert,Erwan Bigan,Marcel Levy Nogueira,Loïc Paulevé,Sabine Peres,Laurent Schwartz

doi:10.1186/s12976-015-0005-2

Abstract

The different phases of the eukaryotic cell cycle are exceptionally well-preserved phenomena. DNA decompaction, RNA and protein synthesis (in late G1 phase) followed by DNA replication (in S phase) and lipid synthesis (in G2 phase) occur after resting cells (in G0) are committed to proliferate. The G1 phase of the cell cycle is characterized by an increase in the glycolytic metabolism, sustained by high NAD+/NADH ratio. A transient cytosolic acidification occurs, probably due to lactic acid synthesis or ATP hydrolysis, followed by cytosolic alkalinization. A hyperpolarized transmembrane potential is also observed, as result of sodium/potassium pump (NaK-ATPase) activity. During progression of the cell cycle, the Pentose Phosphate Pathway (PPP) is activated by increased NADP+/NADPH ratio, converting glucose 6-phosphate to nucleotide precursors. Then, nucleic acid synthesis and DNA replication occur in S phase. Along with S phase, unpublished results show a cytosolic acidification, probably the result of glutaminolysis occurring during this phase. In G2 phase there is a decrease in NADPH concentration (used for membrane lipid synthesis) and a cytoplasmic alkalinization occurs. Mitochondria hyperfusion matches the cytosolic acidification at late G1/S transition and then triggers ATP synthesis by oxidative phosphorylation. We hypothesize here that the cytosolic pH may coordinate mitochondrial activity and thus the different redox cycles, which in turn control the cell metabolism.

Highlights

For several years a number of studies have been conducted, in the field of the bioenergetic origin of life [1]
The latter is enhanced by a high glycolytic rate consuming Nicotinamide adenine dinucleotide (NAD)+ and Adenosine diphosphate (ADP) species for cytoplasmic glucose conversion into pyruvate, generating NADH and adenosine triphosphate (ATP) molecules
The pHi increase towards alkalinization is reported to favor global acetylation of histone, to when “resting cells are induced to proliferate”. These results suggest the intertwined relationship between the metabolic cell cycle balancing the NAD+/NADH and ATP/ADP ratios through intracellular pH oscillations

Summary

Background

A number of studies have been conducted, in the field of the bioenergetic origin of life [1]. Eukaryotic cells, at least, exhibit two opposite metabolisms: anabolic reactions, which consist in biomass synthesis and catabolic reactions, leading to the breakdown of macromolecules for energetic use These two aspects of cell metabolism are managed by biochemical and biophysical oscillators, including reductive and oxidative (redox) couples, the most important ones being Nicotinamide Adenine Dinucleotide (NAD+/NADH) and Nicotinamide da Veiga Moreira et al Theoretical Biology and Medical Modelling (2015) 12:10. From the point of view of the central carbon metabolism (CCM), (Fig. 1), the quiescent cells (in G0) have a basal oxidative metabolism, whereas, in proliferating cells, the carbon flux is rewired to biomass synthesis and cell growth [3] The latter is enhanced by a high glycolytic rate consuming NAD+ and ADP species for cytoplasmic glucose conversion into pyruvate, generating NADH and ATP molecules.

Redox oscillation in dividing cells

Conclusion