UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult

Abstract

Background Neuronal death due to over-oxidative stress responses defines the pathology of cerebral ischemic/reperfusion (I/R) insult. Ferroptosis is a form of oxidative cell death that is induced by disruption of the balance between antioxidants and pro-oxidants in cells. However, the potential mechanisms responsible for cerebral I/R-induced ferroptotic neuronal death have not been conclusively determined. UBIAD1, is a newly identified antioxidant enzyme that catalyzes coenzyme Q10 (CoQ10) and vitamin K2 biosynthesis in the Golgi apparatus membrane and mitochondria, respectively. Even though UBIAD1 is a significant mediator of apoptosis in cerebral I/R challenge, its roles in ferroptotic neuronal death remain undefined. Therefore, we investigated whether ferroptotic neuronal death is involved in cerebral I/R injury. Further, we evaluated the functions and possible mechanisms of UBIAD1 in cerebral I/R-induced ferroptotic neuronal death, with a major focus on mitochondrial and Golgi apparatus dysfunctions. Results Ferroptosis occurred in cerebral I/R. Ferroptotic neuronal death promoted cerebral I/R-induced brain tissue injury and neuronal impairment. UBIAD1 was expressed in cerebral tissues and was localized in neurons, astrocytes, and microglia. Under cerebral I/R conditions overexpressed UBIAD1 significantly suppressed lipid peroxidation and ferroptosis. Moreover, upregulated UBIAD1 protected against brain tissue damage and neuronal death by alleviating I/R-mediated lipid peroxidation and ferroptosis. However, UBIAD1 knockdown reversed these changes. Enhanced UBIAD1-mediated ferroptosis elevated the antioxidative capacity by rescuing mitochondrial and Golgi apparatus dysfunction in cerebral I/R-mediated neuronal injury. They improved the morphology and biofunctions of the mitochondria and Golgi apparatus, thereby elevating the levels of SOD, T-AOC and production of CoQ10, endothelial nitric oxide synthase (eNOS)-regulated nitric oxide (NO) generation as well as suppressed MDA generation. Conclusions The neuroprotective agent, UBIAD1, modulates I/R-mediated ferroptosis by restoring mitochondrial and Golgi apparatus dysfunction in damaged brain tissues and neurons, thereby enhancing antioxidative capacities. Moreover, the rescue of impaired mitochondrial and Golgi apparatus as a possible mechanism of regulating ferroptotic neuronal death is a potential treatment strategy for ischemic stroke. Graphical Abstract

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

“…In nonmitochondrial systems, CoQ10 is involved in regulating lipid peroxidation, paralleling the GPX4 pathway in ferroptosis [ 98 ]. Huang et al [ 16 ] demonstrated that UBIAD1 was upregulated during cerebral I/R, which suppressed lipid peroxidation and ferroptosis and exerted neuroprotective effects. UBIAD1 alleviated cerebral I/R-mediated ferroptotic neuronal death by enhancing antioxidant capacities by ameliorating mitochondria and Golgi apparatus dysfunction, suggesting that restoring impaired mitochondria and the Golgi apparatus is beneficial in ameliorating cerebral I/R injury.…”

Competing endogenous RNA network analysis of the molecular mechanisms of ischemic stroke

“…NO maintains endothelial function by promoting vasodilation and preventing vascular smooth muscle cell proliferation, platelet aggregation, and leukocyte adhesion [ 50 ]. The biosynthesis process of NO has also been found to associate with brain tissue damage and neuronal ferroptosis in the pathology of cerebral ischemic/reperfusion [ 51 ]. The KEGG results showed that the DETmRNAs were mainly enriched in the Toll-like receptor signaling pathway and the NF kappa B signaling pathway.…”

Angong Niuhuang Pill ameliorates cerebral ischemia/reperfusion injury in mice partly by restoring gut microbiota dysbiosis

“…Moreover, enrichment of Alloprevotella may be associated with an increase in serum trimethylamine N-oxide ( Cheng et al, 2017 ), and the latter is a potential causative factor of first and recurrent stroke ( Nam, 2019 ). Additionally, the abundance of fecal Alloprevotella was negatively correlated with serum total antioxidant activity ( Wang et al, 2021 ), and enhancing antioxidative capacity was found to be beneficial for alleviating cerebral ischemia/reperfusion insult ( Huang et al, 2022 ). All these data indicate that ANP administration can protect against stroke by decreasing the abundance of Prevotellaceae and Alloprevotella in the gut.…”