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Fig. 2 | Theoretical Biology and Medical Modelling

Fig. 2

From: Cell cycle progression is regulated by intertwined redox oscillators

Fig. 2

The logic of metabolic cell cycle. Cytosolic NAD+/NADH, NADP+/NADPH, ATP/ADP ratios and intracellular pH (pHi) are reported to oscillate through eukaryotic cell cycle. Mitosis is often described as a catastrophic event where microtubule depolymerization and ATP-dependent pumps « burn » the ATP stock by ATP hydrolysis. This decreases the ATP/ADP ratio. In parallel, the intracellular pH is reported to decrease and reaches its stationary phase in quiescent cells (G0). To our knowledge, there are no data on NAD+/NADH and NADP+/NADPH redox ratios during mitosis. In early G1 phase the increased glycolytic pathway matches a transient acidic pHi before cytosol alkalinization. This is often assumed to be linked to lactate synthesis. Lactate dehydrogenase enzyme catalyses pyruvate conversion to lactic acid by using NADH as coenzyme. NAD+/NADH ratio is high in G1 and decreases until reaching its minimal value in S phase. NADPH consuming pathway such as ROS conversion to reduced species is known to trigger cell cycle entry and enhances PPP by increasing the NADP+/NADPH redox ratio in S phase. This is a necessary step for nucleic nucleotide synthesis. During this phase cytosolic acidification, probably due to glutaminolysis, meets hyperfused mitochondria where ATP synthesis takes place. NAD + −dependent histone synthesis is thought to decrease the NAD+/NADH ratio. In G2, both free ATP concentration and pHi reach their maximal value, high and alkaline, respectively. NADPH consumption during fatty acids synthesis may increase NADP+/NADPH ratio in G2. NAD+/NADH ratio is reported to increase in G2. This could be explain by increased shuttling pathways such as malate/citrate one, permiting NAD+ synthesis from oxaloacetate to malate conversion

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