Cell Cycle and Metabolism

The past decades have witnessed significant advances in our understanding of cell-cycle regulation. However, while the genes and enzymes that regulate cell-cycle progression have been intensely investigated, our understanding on how cells regulate energy (the ‘fuel’) generation and consumption during these processes has lagged. Early work in sea urchin embryos and mammalian cells suggested that cellular energy accumulates during interphase but is depleted in the later stages of mitosis. Both the initiation and completion of DNA synthesis and mitosis are energy-dependent and require oxidative phosphorylation (OXPHOS) in plant and animal cells. Not surprisingly, the control of mitochondrial function and energy generation is integrated in the same regulatory networks that control cell fate decisions, including cell proliferation, differentiation, and death. These networks may have implications for the design and evaluation of possible therapeutic strategies against human disease, including cancer.

Both oxidative phosphorylation (OXPHOS) and glycolysis seem to be generally upregulated during the cell cycle and participate in the generation of energy required for DNA synthesis and chromosome segregation. The morphological changes of mitochondria during the cell cycle are likely to be connected with such metabolic fluctuations, although the exact functional consequences of these changes are not well characterized. OXPHOS is induced early in G1 and it possibly remains active during the whole cell cycle, even in mitosis when mitochondria are fragmented as a result of Cdk-dependent activation. Glycolysis is also modulated by Cdks and the cell-cycle proteolytic machinery at multiple levels, and this control may lead to specific activation during G1/S phase or G2 depending on the cellular setting. Conversely, defects in the energy capacity of the cell result in cell-cycle arrest by altering Cdk activity or triggering specific cell-cycle checkpoints.

 

However, despite recent advances in understanding the connections between the control of energy and the cell cycle, the molecular connections between the generation of energy and cell-cycle progression remain obscure, at least in part due to technical limitations and contradictory observations. In addition, how major mitogenic pathways are able to coordinate energy generation with cell cycle progression is mostly unknown. Both RAS-ERK and PI3K-mTOR participate in these processes but we do not have a clear picture of how this coordination is achieved in different cell types or different biological scenarios.

It is also well established that both cell cycle regulation and metabolic control are altered in tumor cells. Both individual processes are considered of interest for cancer therapy efforts. Rapidly proliferating cells, such as cancer cells, use aerobic glycolysis to support cell division, a feature known as the Warburg effect. A possible function for glycolysis is to provide intermediates for generating biomass in rapidly proliferating cells. Our group reported that this dependence on glycolysis is even more obvious after challenging cancer cells with mitotic inhibitors because this leads to exhaustion of mitochondria during prolonged mitotic arrest.

How to use this information to treat cancer is not yet obvious, but advances in the next few years will undoubtedly provide the proper framework to transfer this knowledge to the clinic.

Mitochondrial Respiration and Glycolysis in Mitosis (Salazar-Roa & Malumbres, Trends Cell Biol, 2017)

·Major questions and specific interests

Our laboratory is interested in addressing some specific questions with relevance in normal physiology and malignant transformation.

Which are the major links between cell cycle progression and metabolic regulation?

Are these processes controlled by cell cycle kinases and phosphatases?

Does metabolic reprogramming have consequences in cell proliferation?

Do cancer cells coordinately change their cell cycle and metabolic consequences?

How major regulatory pathways such as RAS- or PI3K-dependent routes coordinate cell cycle progression with metabolic changes?

Is this control specifically regulated during the different cell cycle phases?

Which of these mechanisms can be used for cancer therapy?

Technical challenges

Some of the difficulties in the analysis of cell cycle and metabolism arise from technical problems, including the lack of proper measurement tools to evaluate metabolic intermediates during cell-cycle progression.

Cell-cycle phases are typically studied after arrest with different chemicals, generating artefactual states that are difficult to evaluate. Results from experimental assays referring to G1 using DNA-replication inhibitors, or to Mitosis using microtubule poisons, are likely to be a consequence of these arresting/synchronization protocols, rather than specific features of G1 or M cells.

There are multiple ‘cell cycles’ in the different cell types in mammals. Data for some cell types may not apply to others, making it difficult to obtain conclusions of general applicability.

In addition, cells are very dynamic both in vivo (also in vitro) and quantitative metabolic studies on time are quite difficult technically. For instance, somatic cell reprogramming from differentiated cells to induced pluripotent stem cells is thought to require a shift from OXPHOS to glycolysis, and this exemplifies the dynamic changes that metabolism may suffer during any changes in culture or manipulation of cells.

Culture conditions, in general, are known to increase the requirement for specific cell cycle regulators and very likely to induce profound changes in metabolism, which are not well understood yet.

The special metabolic regulation of tumor cells has been studied quite in detail. However, how these changes accompany malignant transformation is unclear. In addition, tumor heterogeneity makes taking direct measurements difficult and may account for the fluctuating levels of OXPHOS and glycolysis within the same tumor.

Further reading

Cai, L. and Tu, B.P. (2012) Driving the cell cycle through metabolism. Annu. Rev. Cell Dev. Biol. 28, 59–87.

Doménech, E., Maestre, C., Esteban-Martínez, L., Partida, D., Pascual, R., Fernández-Miranda, G., Seco, E., Campos-Olivas, R., Pérez, M., Megias, D., Allen, K., López, M., Saha, A.K., Velasco, G., Rial, E., Méndez, R., Boya, P., Salazar-Roa, M. and Malumbres, M. (2015) AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. Nat. Cell Biol. 17, 1304–1316.

Hydbring, P., Malumbres, M. and Sicinski, P. (2016) Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat. Rev. Mol. Cell. Biol. 17, 280-292.

Lee, I.H. & Finkel, T. (2013) Metabolic regulation of the cell cycle. Curr. Opin. Cell Biol. 25, 724–729.

Lunt, S.Y. & Vander Heiden, M.G. (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464.

Mishra, P. and Chan, D.C. (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat. Rev. Mol. Cell Biol. 15, 634–646.

Pederson, T. (2003) Historical review: an energy reservoir for mitosis, and its productive wake. Trends Biochem. Sci. 28, 125–129.

Salazar-Roa, M. & Malumbres, M. (2017) Fueling the cell division cycle. Trends Cell Biol. 27, 69-81.

Other Projects

Cell cycle targets & Cancer
Cell proliferation & differentiation: genetics & epigenetics
Pluripotency & Regenerative medicine