Fig. 3: The role of ROS in apoptosis.

Apoptotic pathways can be classified into two categories: extrinsic apoptotic pathways triggered by cell death receptors, and intrinsic apoptotic pathways involving mitochondria. Mitochondria serve as the primary intracellular source of ROS, emanating from electron leakage within the respiratory electron transport chain (ETC). The activation of mitogen-activated protein kinase 14 (MAPK14/p38) or ER stress by ROS influences this balance through anti-apoptotic BCL2 and pro-apoptotic BAX, which results in the release of apoptotic molecules, such as cytochrome c (CYCS). CYCS’s release into the cytoplasm activates initiator caspase 9 (CASP9). ROS may increase the expression of the tumor suppressor protein TP53, which fosters apoptosis not only through the transcriptional regulation of apoptosis-related genes, but also by translocating to the mitochondria. Mitochondrial TP53 interacts with BCL2 family proteins and amplifies mitochondrial membrane permeability independent of transcriptional mechanisms. In addition, ROS is involved in the extrinsic apoptotic pathway through enhancing the expression of both FAS and FASL genes. Eventually, the sequential activation of executor caspase 3 (CASP3) by CASP8 in the extrinsic pathways or CASP9 in the apoptotic pathways initiates apoptosis. On the contrary, NRF2 triggers the transcription of downstream antioxidant genes, effectively neutralizing ROS and mitigating apoptosis.