Fig. 3

The interplay among intracellular compartments in paraptosis development. Paraptosis can be initiated by proteasomal inhibition, which then leads to endoplasmic reticulum (ER) stress. This stress activates the unfolded protein response (UPR), leading to mitochondrial dysfunction and alterations in nuclear transcription and translation. Mitochondrial dysfunction and imbalances in redox systems increase the production of reactive oxygen species (ROS). Elevated ROS levels further suppress proteasome activity, exacerbate ER stress and the UPR, and activate transcription and translation. This, in turn, further disrupts mitochondrial function and intracellular redox systems, generating more ROS. Additionally, Ca²⁺ in the ER can act as a signaling messenger, communicating between the ER and mitochondria. Furthermore, some ER and UPR proteins act as transcription factors or co-factors, regulating the expression of new genes and proteins and amplifying the paraptotic lethal program