Question

How do ROS or other reactive species start the apoptosis process via the mitochondria

Answer 1

Reactive oxygen species include superoxide anion (O2−) and the hydroxyl radical (OH-), and hydrogen peroxide (H2O2). ROS stimulate cell cycle when in low amounts. However, in large amount, they can cause oxidative cell damage which trigger apoptosis.

Mitochondrial-dependent apoptosis involves mitochondrial permeability transition pore (MPTP) complex. It is composed of cyclophillin D present in inner mitochondrial membrane. ROS activates intrinsic pathway of apoptosis in mitochondria. ROS can activate the p53 and /or c-Jun N terminal kinase or JNK. These pathways activate the Bcl-2 proteins. Bcl-2 inhibits the functions of ant-apoptotic proteins such as Bad, Bax, Puma, Noxa and Bak. ROS also depolarizes the mitochondrial membrane, which cause opening of complex of Bak/Bax on the outer mitochondrial membrane will activate DNA fragmentation and apoptosis. This causes release of AIF, Endo G, cytochrome c and Smac/Diablo. This release in cytosol will activate DNA fragmentation. Cytochrome c, released due to oxidation of cardiolipin by ROS, will complex with Apaf-1 and pro-caspase 9 will form apoptosome complex in the cytosol. This activates caspase-9 activation, which then activates caspase-3. Cellular proteins are then cleaved by caspase -3 causing apoptosis. AIF and Endo G will translocate to nucleus where they can activate DNA fragmentation. Thus, ROS will induce mitochondrial DNA fragmentation and degrades proteins resulting in apoptosis.