Dataset Information

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.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8981649 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Huang Yan Y Liu Jianyang J He Jialin J Hu Zhiping Z Tan Fengbo F Zhu Xuelin X Yuan Fulai F Jiang Zheng Z

Cell & bioscience 20220404 1

<h4>Background</h4>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 (CoQ1 ...[more]

PMID: 35379328

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Project description:The formation and life-long growth of the ocular lens depends on the continuous differentiation of lens epithelial cells into lens fiber cells. To achieve their mature structure and transparent function, newly formed lens fiber cells undergo a series of cellular remodeling events including the complete elimination of cellular organelles to form the lens organelle-free zone (OFZ). To date, the mechanisms and requirements for organelle elimination by lens fiber cells remain to be fully elucidated. In previous studies, we detected the presence of mitochondria contained within autophagolysosomes throughout human and chick lenses suggesting that proteins targeting mitochondria for degradation by mitophagy could be required for the elimination of mitochondria during OFZ formation. Consistently, high-throughput RNA sequencing of microdissected embryonic chick lenses revealed that expression of a protein that targets mitochondria for elimination during erythrocyte formation, called BCL2 interacting protein 3-like (BNIP3L/NIX), peaks in the region of lens where organelle elimination occurs. To examine the potential role for BNIP3L in the elimination of mitochondria during lens fiber cell remodeling, we analyzed the expression pattern of BNIP3L in newborn mouse lenses, the effect of its deletion on organelle elimination and its co-localization with lens organelles. We demonstrate that the expression pattern of BNIP3L in the mouse lens is consistent with it playing an important role in the elimination of mitochondria during lens fiber cell organelle elimination. Importantly, we demonstrate that deletion of BNIP3L results in retention of mitochondria during lens fiber cell remodeling, and, surprisingly, that deletion of BNIP3L also results in the retention of endoplasmic reticulum and Golgi apparatus but not nuclei. Finally, we show that BNIP3L localizes to the endoplasmic reticulum and Golgi apparatus of wild-type newborn mouse lenses and is contained within mitochondria, endoplasmic reticulum and Golgi apparatus isolated from adult mouse liver. These data identify BNIP3L as a novel requirement for the elimination of mitochondria, endoplasmic reticulum and Golgi apparatus during lens fiber cell remodeling and they suggest a novel function for BNIP3L in the regulation of endoplasmic reticulum and Golgi apparatus populations in the lens and non-lens tissues.

Dataset Information

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

Background

Results

Conclusions

Publications

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

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