Mitochondria, Bioenergetics and Apoptosis in Cancer

The elements of the electron transport chain are not uniformly distributed along the inner membrane. ATP synthase (Complex V) forms dimers. The other four complexes form resparisomes. The mitochondrial inner membrane is folded into cristae, which remodel in response to metabolic demand as well as cell death pathway signals (apoptosis). The cristae both effect and are affected by the electron transport chain. The membrane potential and pH gradient are not uniform along the inner membrane. The cristae create pockets of acidic regions, and the pH changes up to 0.3 between the ATP synthase (which consumes the energy stored in the membrane) and the resparisomes. The spatial and temporal dependence of these quantities is not possible to assay with current technology. Changes in the mitochondrial cristae (cristae remodeling) are an important step in apoptosis, and a potential target for future pharmacological manipulation. Until recently, the dual roles of mitochondria in ATP production (bioenergetics) and apoptosis (cell life/death decision) were thought to be separate. New evidence points to a more intimate link between these two functions, mediated by the remodeling of the mitochondrial ultrastructure during apoptosis. While most of the key molecular players that regulate this process have been identified (primarily membrane proteins), the exact mechanisms by which they function are not yet understood. Because resistance to apoptosis is a hallmark of cancer, and because ultimately all chemotherapies are believed to result directly or indirectly in induction of apoptosis, a better understanding of the biophysical processes involved may lead to new avenues for therapy. Until recently, the dual roles of mitochondria in ATP production (bioenergetics) and apoptosis (cell life/death decision) were thought to be separate. New evidence points to a more intimate link between these two functions, mediated by the remodeling of the mitochondrial ultrastructure during apoptosis. While most of the key molecular players that regulate this process have been identified (primarily membrane proteins), the exact mechanisms by which they function are not yet understood. Because resistance to apoptosis is a hallmark of cancer, and because ultimately all chemotherapies are believed to result directly or indirectly in induction of apoptosis, a better understanding of the biophysical processes involved may lead to new avenues for therapy. systematic, ordered process of programmed cell death in response to external stimuli or internal stress. complex that uses electrochemical energy stored in the membrane to convert ADP + Pi to ATP, hence coupling oxidation of nutrients to phosphorylation of ADP (OXPHOS). a proapoptotic member of the BH3-only subset of the BCL-2 family of proteins. BID is activated by cleavage by caspase 8 to form truncated BID (tBID). Other members of this family, which number over 10, include for example BIM (Bcl-2-interacting mediator of cell death). heme protein that has the dual role of shuttling electrons in the ETC and also activating caspases in the cytosol once released from the mitochondria to carry out the process of apoptosis. series of protein complexes on the mitochondrial inner membrane which pump protons across the membrane. believed to be caused by oligomerization of BAX/BAK proteins at the outer membrane, triggered by BID. fluorescent dye used to track membrane potential.