Mitochondria as Potential Targets and Initiators of the Blue Light Hazard to the Retina

Figure 3

Possible pathways of cell death that involve the mitochondria in the presence of oxidative stress. (a) Molecular composition of the mPTP complex. A classic model of the mPTP is illustrated in this figure. mPTP spans the mitochondrial inner and outer membrane, and its core components are formed by ANT and VDAC. Several molecules are mainly involved in the regulation of mPTP: (1) CypD, located in the mitochondrial matrix; (2) creatine kinase (CK), an intermembrane space protein; (3) the outer mitochondrial membrane proteins, including HK and PBR, and those of the Bcl-2 family, such as Bax and Bcl-2. (b) Mitochondria-associated intrinsic apoptosis pathway. The opening of mPTP causes mitochondrial permeabilization; thus, proapoptotic proteins located in the mitochondrial intermembrane space, such as Cyt c, are released into the cytoplasm. Cyt c binds to Apaf-1 to form the apoptosome, which is responsible for the recruitment and cleavage of procaspase-9 to active caspase-9. Subsequently, caspase-9 triggers the downstream caspase cascade, resulting in apoptosis. (c) Mitochondria-associated intrinsic necrosis pathway. The necrosome is formed by RIPK1, RIPK3, and MLKL in the extrinsic necrosis pathway and binds sequentially to PGAM5L and PGAM5S. PGAM5S directly recruits and activates Drp1 on mitochondria, contributing to mitochondrial fragmentation, a common step for both apoptosis and necrosis. (d) AIF-mediated necroptosis pathway. Mitochondrial calpains or cytoplasmic calpains that are translocated to mitochondria in an unclear manner can cleave the full AIF that is embedded into the inner membrane to soluble tAIF, which is transferred across the outer membrane through the Bax protein poles. Chaperoned by CypA, tAIF is redistributed to the nuclear compartment, leading to chromatinolysis, which is regulated by γH2AX and cyclophilin A (CypA).