Figure 1.

Mitochondria: A signalling hub between life and death. (Left) Death receptor activation by complementary ligand binding promotes the recruitment of the adaptor protein FADD and subsequent recruitment, homodimerization and activation of the initiator caspases-8 and 10, which in turn activate executioner caspases-3 and -7 directly to induce apoptosis; this is termed the extrinsic apoptotic pathway. Amplification of this death signal, via the mitochondria is mediated by Caspase-8 cleavage of BID. tBID then drives the translocation to and oligomerisation of BAX and BAK at the outer mitochondrial membrane (OMM), where insertion results in the formation of pores, driving MOMP. This process of intrinsic apoptosis is finely tuned by the activities of pro- and anti- BH3 family members such as MCL-1, BCL-2 and BCL-XL. MOMP results in the release of pro-apoptotic effector proteins including SMAC (Second Mitochondrial-derived Activator) and Cytochrome-c which inhibits anti-apoptotic proteins such as XIAP (X-linked Inhibitor of Apoptosis Protein) and promotes apoptosome formation, respectively, further activating the executioner caspases-3 and 7 and commitment to apoptosis. (Right) Cells uptake glucose via glucose transporters (GLUTs) where it enters the glycolytic cascade, a series of enzymatic reactions that ultimately yield ATP and NADH, terminating in pyruvate. High levels of pyruvate inhibit the metabolic process, and so pyruvate is either converted to Acetyl-CoA for further metabolism in the TCA Cycle or converted to lactate (glycolysis endpoint) which is exported from the cell into the extracellular space via MCT transporters. The TCA cycle and subsequent Electron Transport Chain (ETC) oxidises Acetyl-CoA to generate energy and biosynthetic intermediates to fuel lipid, amino acid and nucleotide synthesis. The ETC relies on an intact mitochondrial membrane potential to provide the proton gradient along which to transport electrons through each complex, ultimately resulting in the production of ATP through ATP Synthase. An important by-product from the ETC are reactive oxygen species (ROS) which can have widespread pro- and anti-tumourigenic properties. Abbreviations: FADD: Fas-Associated Death Domain, tBID: Truncated-BID, SMAC: Second Mitochondrial-derived Activator, XIAP: X-linked Inhibitor of Apoptosis Protein, MCL-1: Myeloid Cell Leukaemia-1, BCL-2/BCL-XL (B-Cell CLL/Lymphoma-2/XL), MPTP: Mitochondrial Permeability Transition Pore, ATP: Adenosine Triphosphate, NADPH: Nicotinamide Adenine Dinucleotide Phosphate Hydrogen, ROS: Reactive Oxygen Species.