Cell biology. Metabolic control of cell death

Abstract

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.

Figure 1. Metabolic checkpoints in cell death regulation

Several metabolic checkpoints are in place to convert metabolic perturbations (signals), which are detected by specific systems (sensors), into vital or lethal stimuli that are dispatched to components of the cell death-regulatory machinery (effectors) through one or more signaling nodes (transducers). These include (but are not limited to): the mitochondrial checkpoint, in part impinging on the so-called mitochondrial permeability transition (MPT) (1); the AMPK-TORC1 checkpoint, which is based on the very short half-life of anti-apoptotic proteins such as FLIP_L and MCL-1 (2); the autophagy checkpoint, which is extensively interconnected with other checkpoints (3); the acetyl-CoA/CoA checkpoint, which control cell death through both transcriptional and post-translational mechanisms (4); the HIF-1 checkpoint, integrating signals about oxygen availability and tricarboxylic acid (TCA) cycle proficiency (5); the endoplasmic reticulum (ER) stress checkpoint, which operates by altering the abundance of multiple BH3-only proteins (6); as well as the p53 checkpoint, detecting the availability of non-essential amino acids and converting it into an adaptive or lethal response (7). Glc, glucose; MPT, mitochondrial permeability transition; OXPHOS, oxidative phosphorylation; PEP, phosphoenolpyruvate.

Figure 2. Major signal transduction cascades leading to active cell death

The ligation of death receptor such as TNFR1 generally results in the assembly of a supramolecular complex at the inner leaflet of the plasma membrane known as a death-inducing signaling complex (DISC), which is under the control of FLIP_L. By promoting the activation of CASP-8, the DISC directly ignites the caspase cascade that is responsible for apoptotic cell death (1). Similarly, the executioner caspase cascade can be set off upon mitochondrial outer membrane permeabilization (MOMP) (2) or the so-called mitochondrial permeability transition (MPT) (3), owing to the release into the cytosol of caspase activators as well as to the engagement of caspase-independent mechanisms. Death receptor-elicited apoptosis and MOMP are not entirely disconnected, as in some cells CASP-8 cleaves BID to generate a MOMP-promoting factor. In some settings, MPT can trigger necrotic forms of cell death, at least in part owing to the release of AIF, a mitochondrial protein with latent endonucleolytic activity that is also involved in the PARP1-dependent lethal cascade elicited by alkylating DNA damage (4). Of note, the ligation of TNFR1 in the presence of Z-VAD-fmk (a pan caspase inhibitor), alone or combined with a Smac mimetic, drives a specific instance of regulated necrosis known as necroptosis (5). Necroptosis, which is inhibited by a supramolecular complex involving FADD, CASP-8 and FLIP_L, obligatorily relies on the formation of MLKL oligomers that relocalize to the plasma membrane and disrupt ionic homeostasis. CYPA, cyclophilin A (official name: peptidylprolyl isomerase A); CYTC, holocytochrome c; ER, endoplasmic reticulum; ROS, reactive oxygen species; TRADD, TNFRSF1A-associated via death domain; TRP, transient receptor potential cation channel; XIAP, X-linked inhibitor of apoptosis.

Figure 3. The ATP synthasome and its interacting partners

A,B. The term ‘ATP synthasome’ refers to the supramolecular complex composed of the F₁F_O-ATP synthase, ANT and PIC. The F₁F_O-ATP synthase harnesses the electrochemical gradient generated by the respiratory chain across the inner mitochondrial membrane (IMM) to catalyze the synthesis of ATP, whereas PIC and ANT ensure the availability of inorganic phosphate and ADP, respectively. The ATP synthasome interacts with CYPD, a protein of the mitochondrial matrix, and the VDAC1-HKII complex, which is assembled at the outer mitochondrial membrane (OMM). On one hand, these interactions allow ATP molecules produced by the F₁F_O-ATP synthase to be channeled to the mitochondrial surface and support the HKII-mediated conversion of glucose into glucose-6-phosphate (G6P). On the other hand, they place the ATP synthasome in a privileged position to contribute to (or regulate) the so-called ‘permeability transition pore complex’ (PTPC), the supramolecular entity that mediates the mitochondrial permeability transition (MPT). CK, creatine kinase (official name: creatine kinase, mitochondrial 1, ubiquitous) IMS, intermembrane space. Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).