Metabolic control of cell death

Background 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. Advances 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 F1FO 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. Outlook 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 stimuli, which are dispatched to components of the cell death–regulatory machinery (targets) through one or more signaling nodes (transducers). Metabolic checkpoints therefore integrate various “bits” of information into a biological response that inhibits or promotes cell death. It is tempting to speculate that a detailed understanding of metabolic checkpoints might allow for the development of novel pharmacological approaches that block or stimulate cell death by inducing specific metabolic alterations. Such interventions may be useful for the treatment of pathologies involving unwarranted cell death, such as ischemic, infectious, and neurodegenerative disorders, as well as pathological states in which the cellular demise is intrinsically blocked, as seen in autoimmune diseases and neoplastic conditions. Beyond their contribution to basic metabolism, the major cellular organelles, in particular mitochondria, can determine whether cells respond to stress in an adaptive or suicidal manner. Thus, mitochondria can continuously adapt their shape to changing bioenergetic demands as they are subjected to quality control by autophagy, or they can undergo a lethal permeabilization process that initiates apoptosis. Along similar lines, multiple proteins involved in metabolic circuitries, including oxidative phosphorylation and transport of metabolites across membranes, may participate in the regulated or catastrophic dismantling of organelles. Many factors that were initially characterized as cell death regulators are now known to physically or functionally interact with metabolic enzymes. Thus, several metabolic cues regulate the propensity of cells to activate self-destructive programs, in part by acting on nutrient sensors. This suggests the existence of “metabolic checkpoints” that dictate cell fate in response to metabolic fluctuations. Here, we discuss recent insights into the intersection between metabolism and cell death regulation that have major implications for the comprehension and manipulation of unwarranted cell loss.