Fig. 8: Proposed mechanism of Me₂NNMe₂-induced paraptosis.

Me₂NNMe₂ accumulates in the ER, where it inhibits the reductive potential of PDI. This leads to the disruption of the ER thiol redox homeostasis, which in turn activates PERK signaling and release of Ca²⁺ ions from the ER. While PERK activation is followed by CHOP translocation into the nucleus and increased transcription of PDI and ero1L-α, released Ca²⁺ ions are taken up by mitochondria. Prolonged Ca²⁺ imbalance initiates organelle swelling and mitochondrial membrane depolarization. NAC and 1-thioglycerol can ameliorate thiol redox imbalances. MAPKs further regulate Ca²⁺ and thiol redox homeostasis, which can be inhibited by U0126