PDI-mediated S-nitrosylation of DRP1 facilitates DRP1-S616 phosphorylation and mitochondrial fission in CA1 neurons

• Published in: Cell death & disease Vol. 9; no. 9; pp. 869 - 13
• Main Authors: Lee, Duk-shin, Kim, Ji-Eun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.08.2018; Springer Nature B.V
• Subjects: 13/1; 13/51; 82/29; 82/80; Animals; Antibodies; Arginine; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cysteine - metabolism; Disease Models, Animal; Dynamin; Dynamins - metabolism; Elongation; Epilepsy; Immunology; Life Sciences; Male; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - physiology; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - physiology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; NG-Nitroarginine methyl ester; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Nitric-oxide synthase; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Physiology; Protein disulfide-isomerase; Protein Disulfide-Isomerases - metabolism; Proteolysis - drug effects; Rats; Rats, Sprague-Dawley; Serine; Serine - metabolism; Status Epilepticus - metabolism; Status Epilepticus - pathology; Thioredoxin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0910-5

Dynamin-related protein 1 (DRP1) is a key molecule to regulate mitochondrial fission. DRP1 activity is modulated by phosphorylation and S -nitrosylation on serine and cysteine residues, respectively. However, it is still unexplored whether S -nitrosylation of DRP1 affects its phosphorylation. In the present study, we found that N ω -nitro- l -arginine methyl ester hydrochloride ( l -NAME, a NOS inhibitor) abolished S -nitrosylated (SNO-DRP1) and DRP1-serine (S) 616 phosphorylation levels in CA1 neurons under physiological condition. l -NAME led to mitochondrial elongation. In spite of the sustained NO synthesis, status epilepticus (a prolonged seizure activity, SE) diminished SNO-DRP1 and DRP1-S616 levels in CA1 neurons, accompanied by the reduced protein disulfide isomerase (PDI) expression and mitochondrial elongation. SE did not influence thioredoxin 1 (Trx1, a denitrosylating enzyme) activity, which was unaffected by l -NAME under physiological and post-SE condition. PDI knockdown decreased SNO-DRP1 and DRP1-S616 levels concomitant with mitochondrial elongation in CA1 neurons without altered NO synthesis under physiological condition. These findings indicate that PDI may be a NO donor of DRP1 to regulate DRP1-S616 phosphorylation, independent of Trx1 activity. Therefore, we suggest that PDI-mediated S -nitrosylation of DRP1 may be one of the major regulatory modifications for mitochondrial dynamics.