The study investigates the role of S-nitrosylation of dynamin-related protein 1 (Drp1) in mitochondrial fission and neuronal injury, particularly in the context of Alzheimer's disease (AD). Nitric oxide (NO), produced in response to β-amyloid protein (Aβ), triggers mitochondrial fission, synaptic loss, and neuronal damage. The researchers found that NO induces S-nitrosylation of Drp1, forming SNO-Drp1, which promotes mitochondrial fragmentation and neuronal injury. This process is regulated by the S-nitrosylation of a specific cysteine residue, Cys644, located in the GTPase effector domain (GED) of Drp1. SNO-Drp1 formation was observed in both in vitro and in vivo models, including human AD brains, where it was significantly elevated. The study also demonstrated that preventing SNO-Drp1 formation by cysteine mutation abrogated neurotoxic events. Furthermore, SNO-Drp1 was found to increase GTPase activity and dimerize Drp1, contributing to mitochondrial fragmentation and synaptic damage. These findings suggest that SNO-Drp1 may serve as a biomarker for AD and that targeting Drp1 could be a potential therapeutic approach to counteract neurodegenerative disorders associated with nitrosative stress and mitochondrial dysfunction.The study investigates the role of S-nitrosylation of dynamin-related protein 1 (Drp1) in mitochondrial fission and neuronal injury, particularly in the context of Alzheimer's disease (AD). Nitric oxide (NO), produced in response to β-amyloid protein (Aβ), triggers mitochondrial fission, synaptic loss, and neuronal damage. The researchers found that NO induces S-nitrosylation of Drp1, forming SNO-Drp1, which promotes mitochondrial fragmentation and neuronal injury. This process is regulated by the S-nitrosylation of a specific cysteine residue, Cys644, located in the GTPase effector domain (GED) of Drp1. SNO-Drp1 formation was observed in both in vitro and in vivo models, including human AD brains, where it was significantly elevated. The study also demonstrated that preventing SNO-Drp1 formation by cysteine mutation abrogated neurotoxic events. Furthermore, SNO-Drp1 was found to increase GTPase activity and dimerize Drp1, contributing to mitochondrial fragmentation and synaptic damage. These findings suggest that SNO-Drp1 may serve as a biomarker for AD and that targeting Drp1 could be a potential therapeutic approach to counteract neurodegenerative disorders associated with nitrosative stress and mitochondrial dysfunction.