Metabolic regulation of the cell cycle

Abstract

There is a growing appreciation that metabolic signals are integrated and coupled to cell cycle progression. However, the molecular wiring that connects nutrient availability, biosynthetic intermediates and energetic balance to the core cell cycle machinery remains incompletely understood. In this review, we explore the recent progress in this area with particular emphasis on how nutrient and energetic status is sensed within the cell to ultimately regulate cell growth and division. The role these pathways play in normal cell function including stem cell biology is also discussed. Furthermore, we describe the growing appreciation that dysregulation of these pathways might contribute to a variety of pathological conditions including metabolic diseases and tumor formation.

Figure 1

Activation of mTORC1 occurs at the lysosomal surface. Amino acid levels are sensed through an inside-out mechanism using the lysosomal V-ATPase. The sensing mechanism also includes the Ragulator complex, which acts as a guanine nucleotide exchange factor (GEF) for the Rag family of GTP binding proteins. The activity of mTOR is negatively regulated by AMPK that senses AMP and ADP levels during energy depleted conditions, or is activated by a variety of other energy sensors including LKB1.

Figure 2

Mitochondrial dynamics and the cell cycle. Mitochondria can undergo profound alterations in their morphology. Fusion results in elongated, tubulated mitochondria, while fission results in mitochondria that are fragmented. Recent evidence suggests that mitochondrial morphology is coordinated with cell cycle phases with fused mitochondria occurring at the G1/S boundary and fragmented mitochondria occurring more frequently during G2/M.

Figure 3

Stem cell biology and metabolism. Various recent mouse models have linked the intracellular metabolism of stem cells with certain specific alterations. For instance, mice deficient in a variety of kinases (ATM), transcription factors (FoxO family), or chromatin modifiers (Bmi1) exhibit alterations in mitochondrial function or redox homeostasis. Similarly, disruption of genes involved in energy sensing (LKB1) or regulation of metabolic enzymes (PDK2 and PDK4) alter stem cell metabolism. These models in turn appear to exhibit profound defects in stem cell function including alterations in stem cell self-renewal capacity or maintenance of quiescence.