For several decades, intermediate metabolism and signal transduction have been considered two independent entities. On one side stood the catabolic and anabolic reactions that provide cells with the energy and building blocks required for life. On the other side were the cascades of transcriptional events and posttranscriptional modifications that control nearly all cellular processes, including regulated variants of cell death such as apoptosis and regulated necrosis. This somewhat simplistic perception has been instrumental for the detailed characterization of several metabolic circuitries and signaling pathways. However, owing to this theoretical construction, the intimate cross-talk between metabolism and cell death has been largely disregarded until recently, even though organelles with major metabolic functions, such as mitochondria, were shown to play critical roles in regulated cell death nearly 20 years ago.

Metabolic control of cell death. Cells are provided with multiple metabolic checkpoints that sense specific metabolic variables and generate a biological response through one or more transducers and effectors. Such basic checkpoints are highly interconnected, making up a complex network that controls cell fate in response to metabolic perturbations.

It is now clear that metabolism and cell death are deeply intertwined at several levels. Many proteins that mediate vital metabolic functions also have key activities in the transduction of cell death–regulatory signals. An example is holocytochrome c, which not only shuttles electrons between respiratory complex III and IV [hence required for oxidative phosphorylation and mitochondrial adenosine triphosphate (ATP) synthesis] but also promotes the lethal activation of caspases in response to mitochondrial outer membrane permeabilization. Conversely, several proteins that were originally characterized for their capacity to regulate cell death have been found to control metabolic circuitries. This applies to various antiapoptotic members of the Bcl-2 protein family, which play a critical role in the regulation of mitochondrial outer membrane permeabilization in apoptosis and influence intracellular Ca²⁺ fluxes (hence affecting many metabolic activities), the efficacy of mitochondrial ATP synthesis (by binding to the F₁F_O ATP synthase), and autophagic flux (by engaging in physical interactions with beclin-1). Moreover, several metabolic intermediates, including (but not limited to) ATP, acetyl–coenzyme A (CoA), oxidized nicotinamide adenine dinucleotide (NAD⁺), NAD phosphate (NADP⁺), and reactive oxygen species, are intimately involved in signal transduction cascades that influence the propensity of cells to commit to die.

We propose the existence of several “metabolic checkpoints,” that is, refined molecular mechanisms that sense a panel of metabolic variables and emit one or more signals controlling cell fate. Most often, these checkpoints react to metabolic imbalances by activating an organelle-specific or cellwide adaptive response that, at least initially, attempts to reestablish homeostasis. However, when metabolic perturbations are excessively severe or protracted in time, metabolic checkpoints become capable of initiating apoptotic or necrotic forms of regulated cell death. Accumulating evidence indicates that metabolic checkpoints of this type are in place to monitor the ATP/ADP, acetyl-CoA/CoA, NAD⁺/NADH, and NADP⁺/NADPH ratios, as well as the abundance of lipid products, glycosylated proteins, and reactive oxygen species. Perturbations of any such metabolic variables (signals) are detected by specific systems (sensors) and converted into vital or lethal …