Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression

Morales, Carlos R.; Grigoryeva, Lubov S.; Pan, Xuefang; Bruno, L. Travi; Hickson, Gilles R.X.; Ngo, Michael Hung; McMaster, Christopher R.; Samuels, Mark E.; Pshezhetsky, Alexey V.

doi:10.1016/j.ymgmr.2014.09.001

Cited by 8 publications

(10 citation statements)

References 19 publications

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“…A major finding in the Ubiad1 mutant mouse that we report is the effect of the N100S mutation on mitochondrial morphology and biosynthesis. Mitochondria showed evidence of dysfunction as evidenced by disorganization and less distinct cristae inner membranes, similar to what has been described previously for HepG2 cell lines in which UBIAD1 was genetically silenced 14 . There is also one report of mitochondrial abnormality observed by electron microscopy in a patient with SCD 22 .…”

Section: Discussionsupporting

confidence: 83%

“…Expression of ectopic UBIAD1 decreases the cholesterol content of several tested cell lines 13 , but whether this decrease is due to a decrease in cholesterol synthesis, an increase in cholesterol uptake, or an increase in cholesterol efflux from cells was not determined. On the other hand, knockdown of UBIAD1 in HepG2 cells shows no effect on the cholesterol content of these cells 14 . Also, expression of SCD mutated N102S UBIAD1 in human umbilical artery endothelial cells does not alter cellular cholesterol levels compared to cells with normal UBIAD1 expression 8 .…”

Section: Discussionmentioning

confidence: 91%

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A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation

Dong

Jin

Boettler

et al. 2018

Sci Rep

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Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disease in humans, characterized by abnormal deposition of cholesterol and phospholipids in cornea caused by mutations in the UbiA prenyltransferase domain containing 1 (UBIAD1) gene. In this study, we generated a mouse line carrying Ubiad1 N100S point mutation using the CRISPR/Cas9 technique to investigate the pathogenesis of SCD. In vivo confocal microscopy revealed hyper-reflective dot-like deposits in the anterior cornea in heterozygotes and homozygotes. No significant change was found in corneal epithelial barrier function or wound healing. Electron microscopy revealed abnormal mitochondrial morphology in corneal epithelial, stromal, and endothelial cells. Mitochondrial DNA copy number assay showed 1.27 ± 0.07 fold change in homozygotes versus 0.98 ± 0.05 variation in wild type mice (P < 0.05). Lipidomic analysis indicated abnormal metabolism of glycerophosphoglycerols, a lipid class found in mitochondria. Four (34:1, 34:2, 36:2, and 44:8) of the 11 glycerophosphoglycerols species identified by mass spectrometry showed a significant increase in homozygous corneas compared with heterozygous and wild-type mouse corneas. Unexpectedly, we did not find a difference in the corneal cholesterol level between different genotypes by filipin staining or lipidomic analysis. The Ubiad1N100S mouse provides a promising animal model of SCD revealing that mitochondrial dysfunction is a prominent component of the disease. The different phenotype in human and mouse may due to difference in cholesterol metabolism between species.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 91%

A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation

Dong

Jin

Boettler

et al. 2018

Sci Rep

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“…Silencing UBIAD1 in carcinoma cells causes morphological changes in the mitochondria (Morales et al, 2014). These studies of UBIAD1 emphasize its important role in oxidative/nitrosative stress, mitochondrial function, and cholesterol metabolism.…”

Section: Introductionmentioning

confidence: 88%

“…Vitamin K2 is involved in mitochondrial electron transport, ectopic UBIAD1 expression-elevated mitochondrial membrane potential, and ROS/RNS overproduction ( Fredericks et al, 2013a ). Silencing UBIAD1 in carcinoma cells causes morphological changes in the mitochondria ( Morales et al, 2014 ). These studies of UBIAD1 emphasize its important role in oxidative/nitrosative stress, mitochondrial function, and cholesterol metabolism.…”

Section: Introductionmentioning

confidence: 99%

Olfactory Mucosa Mesenchymal Stem Cells Ameliorate Cerebral Ischemic/Reperfusion Injury Through Modulation of UBIAD1 Expression

Liu

Huang

et al. 2020

Front. Cell. Neurosci.

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Mesenchymal stem cells (MSCs) have presented a promising neuroprotective effect in cerebral ischemia/reperfusion (I/R). Olfactory mucosa MSCs (OM-MSCs), a novel source of MSCs located in the human nasal cavity, are easy to obtain and situated for autologous transplantation. The present study was designed to evaluate the neuroprotective effects of OM-MSCs on cerebral I/R injury and the possible mechanisms. In the transient middle cerebral artery occlusion (t-MCAO) model, excessive oxidative stress and increased swollen mitochondria were observed in the peri-infarct cortex. Intravenous injection of OM-MSCs ameliorated mitochondrial damage and restored oxidant/antioxidant imbalance. Using the oxygen glucose deprivation/reperfusion (OGD/R) model in vitro , we discovered that the exposure of mouse neuroblastoma N2a cells to OGD/R triggers excessive reactive oxygen species (ROS) generation and induces mitochondrial deterioration with decreased mitochondrial membrane potential and reduces ATP content. OM-MSC transwell coculture attenuated the above perturbations accompanied with increased UbiA prenyltransferase domain-containing 1 (UBIAD1) expression, whereas these protective effects of OM-MSCs were blocked when UBIAD1 was knocked down. UBIAD1-specific small interfering RNA (siRNA) reversed the increased membrane potential and ATP content promoted by OM-MSCs. Additionally, UBIAD1-specific siRNA blocked the oxidant/antioxidant balance treated by OM-MSCs. Overall, our results suggested that OM-MSCs exert neuroprotective effects in cerebral I/R injury by attenuating mitochondrial dysfunction and enhancing antioxidation via upregulation of UBIAD1.

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“…The structure of the mitochondria is closely related to its function, and mitochondrial structure and functions vary from tissue to tissue 53 . Silencing UBIAD1 causes dramatic morphological changes and cholesterol storage in the mitochondria; this effect thus emphasizes the important role of UBIAD1 in mitochondrial function 54 . Interestingly, mutations in the Drosophila heix gene resulted in abnormal mitochondrial morphology and malfunction 13 , 14 .…”

Section: Discussionmentioning

confidence: 81%

Vitamin K2 Prevents Lymphoma in Drosophila

Dragh

Zhou

Al-Allak

et al. 2017

Sci Rep

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Previous studies have established the anticancer effect of vitamin K2 (VK2). However, its effect on lymphoma induced by UBIAD1/heix mutation in Drosophila remains unknown. Therefore, we aimed to develop an in vivo model of lymphoma for the precise characterization of lymphoma phenotypes. We also aimed to improve the understanding of the mechanisms that underlie the preventative effects of VK2 on lymphoma. Our results demonstrated that VK2 prevents lymphoma by acting as an electron carrier and by correcting the function and structure of mitochondria by inhibiting mitochondrial reactive oxygen species production mtROS. Our work identifies mitochondria as a key player in cancer therapy strategies.

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Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression

Cited by 8 publications

References 19 publications

A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation

A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation

Olfactory Mucosa Mesenchymal Stem Cells Ameliorate Cerebral Ischemic/Reperfusion Injury Through Modulation of UBIAD1 Expression

Vitamin K2 Prevents Lymphoma in Drosophila

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