Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.

Autor: Wang SH; Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, South Korea., Lee DS; Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, South Korea., Kim TH; Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, South Korea., Kim JE; Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, South Korea. jieunkim@hallym.ac.kr., Kang TC; Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, South Korea. tckang@hallym.ac.kr.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Sep 30; Vol. 15 (9), pp. 707. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1038/s41419-024-07050-5
Abstrakt: Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.
(© 2024. The Author(s).)
Databáze: MEDLINE
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