Figure 2.

There are several adverse factors within the mitochondria that, alone or together, can result depolarization of the mitochondria, failure of oxidative phosphorylation, ATP depletion, and apoptosis. Oxidative phosphorylation is the process by which electrons from NADH and FADH2 are transferred through a series of electron carriers in order to generate ATP. 1) Electrons that leak out from one of the complexes of the electron transport chain interact with oxygen to form ROS. Influx of Ca²⁺ from the ER into the mitochondria is regulated by VDAC and MCU. 2) In times of ER‐stress, influx of Ca²⁺ is increased. mPTP consists of VDAC and ANT. Brief, reversible mPTP opening constitutes a housekeeping function by releasing the mitochondria from accumulated ROS and Ca²⁺. 3) Increased levels of ROS and Ca²⁺, however, leads to longer mPTP openings, depolarization, and release op apoptotic factors into the cytosol. Cardiolipin is tightly bound to ANT. 4) Interaction of perioxidized cardiolipin with ANT also leads to activation of the mPTP. 5) Increased mPTP opening can lead to an osmotic imbalance that induces the swelling of the mitochondrial matrix and rupture of the OMM. Cardiolipin is tightly bound to several protein complexes on the IMM, including cytochrome c. 6) Changes in the composition or content of cardiolipin as well as peroxidation of cardiolipin lead to detachment of cytochrome c from cardiolipin, and translocation of cardiolipin to the OMM. 7) Cardiolipin translocation destabilizes the OMM lipid composition which favors the formation of pores, and leads to a disturbed equilibrium of the mitochondria. Cardiolipin translocation to the OMM also results in the recruitment of BAX. 8) BAX assembles into large oligomers and induces pores in the OMM. 9) BAX also works in conjunction with BAK to facilitate the opening of mPTP. In the cytoplasm, cycochrome c binds to the cytosolic protein APAF1 to promote the formation of an “apoptosome,” which leads to activation of caspase‐9 and caspase 3. 10) This results in DNA fragmentation and chromatin condensation.