The tangled circuitry of metabolism and apoptosis

Abstract

For single-cell organisms, nutrient uptake and metabolism are central to the fundamental decision of whether to grow or divide. In metazoans, cell fate decisions are more complex: organismal homeostasis must be strictly maintained by balancing cell proliferation and death. Despite this increased complexity, cell fate within multicellular organisms is also influenced by metabolism; recent studies, triggered in part by an interest in tumor metabolism, are beginning to illuminate the mechanisms through which proliferation, death, and metabolism are intertwined. In particular, work on Bcl-2 family proteins suggests that the signaling pathways governing metabolism and apoptosis are inextricably linked. Here we review the crosstalk between these pathways, emphasizing recent work that illustrates the emerging dual nature of several core apoptotic proteins in regulating both metabolism and cell death.

Figure 1. A summary of metabolic and apoptotic pathways relevant to this review

The left panel summarizes the fate of glucose through glycolysis, the TCA cycle, the pentose phosphate pathway, and lipid synthesis. The right panel outlines the key apoptotic steps addressed in this review. Abbreviations: Glut glucose transporter, HK hexokinase, CoA coenzyme A, NADPH nicotinamide adenine dinucleotide phosphate (reduced), PEP phosphoenolpyruvate, FBP fructose 1,6-bisphosphate, PFK phosphofructokinase, ACL ATP citrate lyase, TCA tricarboxylic acid, tBid truncated Bid, Apaf-1 apoptotic protease activating factor-1, Bcl-2 B cell lymphoma-2.

Figure 2. The dual roles of Bcl-2 family proteins

Aside from their traditional roles in suppressing Bcl-Xl and Mcl-1, Bad and Noxa (when phosphorylated) modulate metabolism by enhancing glucose consumption through glycolysis and the pentose phosphate pathway, respectively. Additionally, Bcl-XL and an N-terminally cleaved form of Mcl-1 localize to the matrix to promote respiration. It is still unclear how these novel metabolic functions of Bcl-2 family proteins may intertwine with their long-studied roles in modulating MOMP.

Figure 3. Model for the metabolic regulation of caspase-2 in Xenopus eggs/oocytes

High NAD+ levels stimulate Sirt1 deacetylase activity, which, in turn, activates pro-survival transcriptional pathways. Additionally, Sirtuin deacetylase activity maintains 14-3-3 in a deacetylated state, permitting binding between 14-3-3 and caspase-2. As NAD+ levels drop, Sirtuin activity diminishes and 14-3-3 becomes acetylated at lysine residues critical for protein-protein interactions. This disrupts 14-3-3/caspase-2 binding, and frees caspase-2 to become active in response to a stress stimulus.