Menaquinone-4 attenuates ferroptosis by upregulating DHODH through activation of SIRT1 after subarachnoid hemorrhage

Jiatong Zhang; Qi Zhu; Zheng Peng; Xiao-Jian Li; Peng-Fei Ding; Sen Gao; Bin Sheng; Yang Liu; Yue Lu; Zong Zhuang; Chun-Hua Hang; Wei Li

doi:10.1016/j.freeradbiomed.2023.11.031

Menaquinone-4 attenuates ferroptosis by upregulating DHODH through activation of SIRT1 after subarachnoid hemorrhage

Free Radic Biol Med. 2024 Jan:210:416-429. doi: 10.1016/j.freeradbiomed.2023.11.031. Epub 2023 Nov 30.

Authors

Jiatong Zhang¹, Qi Zhu², Zheng Peng³, Xiao-Jian Li⁴, Peng-Fei Ding⁵, Sen Gao⁶, Bin Sheng⁷, Yang Liu⁸, Yue Lu⁹, Zong Zhuang¹⁰, Chun-Hua Hang¹¹, Wei Li¹²

Affiliations

¹ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
² Neurosurgical Institute, Nanjing University, China; Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
³ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
⁴ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
⁵ Neurosurgical Institute, Nanjing University, China; Department of Neurosurgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
⁶ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
⁷ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
⁸ Neurosurgical Institute, Nanjing University, China; Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
⁹ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
¹⁰ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
¹¹ Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].
¹² Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China; Neurosurgical Institute, Nanjing University, China. Electronic address: [email protected].

PMID: 38042225
DOI: 10.1016/j.freeradbiomed.2023.11.031

Abstract

Background: Menaquinone-4(MK-4), the isoform of vitamin K2 in the brain, exerts neuroprotective effects against a variety of central nervous system disorders. This study aimed to demonstrate the anti-ferroptosis effects of MK-4 in neurons after SAH.

Methods: A subarachnoid hemorrhage (SAH) model was prepared by endovascular perforation in mice. In vitro hemoglobin stimulation of primary cortical neurons mimicked SAH. MK-4, Brequinar (BQR, DHODH inhibitor), and Selisistat (SEL, SIRT1 inhibitor) were administered, respectively. Subsequently, WB, immunofluorescence was used to determine protein expression and localization, and transmission electron microscopy was used to observe neuronal mitochondrial structure while other indicators of ferroptosis were measured.

Results: MK-4 treatment significantly upregulated the protein levels of DHODH; decreased GSH, PTGS2, NOX1, ROS, and restored mitochondrial membrane potential. Meanwhile, MK-4 upregulated the expression of SIRT1 and promoted its entry into the nucleus. BQR or SEL partially abolished the protective effect of MK-4 on, neurologic function, and ferroptosis.

Conclusions: Taken together, our results suggest that MK-4 attenuates ferroptosis after SAH by upregulating DHODH through the activation of SIRT1.

Keywords: Dihydroorotate dehydrogenase; Early brain injury; Ferroptosis; Sirtuin 1; Subarachnoid hemorrhage; Vitamin K2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries* / metabolism
Dihydroorotate Dehydrogenase
Ferroptosis*
Mice
Rats
Rats, Sprague-Dawley
Sirtuin 1 / genetics
Sirtuin 1 / metabolism
Subarachnoid Hemorrhage* / drug therapy
Subarachnoid Hemorrhage* / metabolism
Vitamin K 2 / pharmacology

Substances

Dihydroorotate Dehydrogenase
menatetrenone
Vitamin K 2
Sirtuin 1