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.