Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress

Shyam, Rajalekshmy; Ogando, Diego G.; Bonanno, Joseph A.

doi:10.3389/fcell.2022.878395

Cited by 8 publications

(8 citation statements)

References 34 publications

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“…When the formation rate of misfolded proteins reaches saturation, it can lead to ER stress [170]. ER stress occurs in CHED [171]. In addition, SLC4A11 was able to adhere to the descemet's membrane.…”

Section: The Other Slc4 Proteinsmentioning

confidence: 99%

“…Furthermore, a dysfunction of SLC4A11 can lead to the generation of mitochondrial ROS, which can damage the mitochondria and promote mitophagy. In the meantime, the function of lysosomes is destroyed and aberrant [171]. Research indicates that patients with CHED mutated by the homozygous SLC4A11 can develop Harboyan syndrome at a later age [173], which can lead to progressive sensorineural hearing loss.…”

Section: The Other Slc4 Proteinsmentioning

confidence: 99%

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Potential Theranostic Roles of SLC4 Molecules in Human Diseases

Zhong,

Dong,

Ruan

et al. 2023

IJMS

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The solute carrier family 4 (SLC4) is an important protein responsible for the transport of various ions across the cell membrane and mediating diverse physiological functions, such as the ion transporting function, protein-to-protein interactions, and molecular transduction. The deficiencies in SLC4 molecules may cause multisystem disease involving, particularly, the respiratory system, digestive, urinary, endocrine, hematopoietic, and central nervous systems. Currently, there are no effective strategies to treat these diseases. SLC4 proteins are also found to contribute to tumorigenesis and development, and some of them are regarded as therapeutic targets in quite a few clinical trials. This indicates that SLC4 proteins have potential clinical prospects. In view of their functional characteristics, there is a critical need to review the specific functions of bicarbonate transporters, their related diseases, and the involved pathological mechanisms. We summarize the diseases caused by the mutations in SLC4 family genes and briefly introduce the clinical manifestations of these diseases as well as the current treatment strategies. Additionally, we illustrate their roles in terms of the physiology and pathogenesis that has been currently researched, which might be the future therapeutic and diagnostic targets of diseases and a new direction for drug research and development.

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Section: The Other Slc4 Proteinsmentioning

confidence: 99%

Section: The Other Slc4 Proteinsmentioning

confidence: 99%

Potential Theranostic Roles of SLC4 Molecules in Human Diseases

Zhong,

Dong,

Ruan

et al. 2023

IJMS

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“…The Slc4a11 -/- mouse shows corneal edema and endothelial cell loss but no guttae 37 . While the Slc4a11 -/- and Col8a2 Q455K mouse models exhibit corneal endothelial dysfunctions, these mice are otherwise healthy with no developmental abnormalities 36–38 .…”

Section: Introductionmentioning

confidence: 99%

“…For instance: the Col8a2 Q455K mouse, which contains an autosomal dominant mutation implicated in early-onset FECD, shows the presence of guttae and corneal endothelial cell loss but no corneal edema 36 . Solute carrier family 4, member 11 (SLC4A11), an inner mitochondrial membrane protein, is highly expressed in the corneal endothelium, and the loss of function of this protein is associated with Congenital Hereditary Endothelial Dystrophy 37,38 and late-onset FECD 26 . The transcript levels of this gene are reduced in the early-onset FECD mouse model 25 .…”

Section: Introductionmentioning

confidence: 99%

Characterization of a novel mouse model for Fuchs Endothelial Corneal Dystrophy

Murugan,

de Campos,

Ghag

et al. 2023

Preprint

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PurposeFuchs Endothelial Corneal Dystrophy (FECD) is a progressive blinding disorder prevalent in 4% of Americans over 40. Corneal transplantation is the standard treatment. Animal models with partial FECD features exist, but a model encompassing all the major disease characteristics is desirable to improve the understanding of the pathogenesis and to identify signaling pathways involved in the disease onset and progression. Such an animal model can be helpful to develop intervention strategies. Here, we developed a mouse model that recapitulates all the features of FECD.MethodLoss of function mutations inSlc4a11and a knock-in mutation inCol8a2(Q455K) are implicated in FECD. Mice with Slc4a11 and Col8a2 mutations in C57BL/6J background were crossed to generate double mutant mice at F2 generation. At five weeks of age, a subset of the animals were fed tamoxifen-enriched chow or standard chow for two weeks, followed by standard chow. Corneal thickness, endothelial cell density, and guttae were measured at 5 (baseline) and 16 weeks of age. Corneas collected from mice at 16 weeks were stained for tight and adherens junctions, and reactive oxygen species. A lactate assay was performed to evaluate the endothelial pump function.ResultsThe double mutant tamoxifen-fed mice showed increased corneal thickness, decreased endothelial cell density, presence of guttae, and elevated stromal lactate levels. The endothelial cells showed altered morphology with disrupted adherens junctions and elevated ROS.ConclusionOverall, this mouse model recapitulates all the important phenotypic features associated with FECD.

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“…Our group analyzed the endoplasmic reticulum stress GRP78, IRE-1α, ATF6, PERK gene by establishing a mouse Zn de ciency model and combining Zn de ciency modeling of hepatocytes (20)(21)(22)(23). We analyzed apoptosis in liver tissues by detecting caspase-12, caspase-9, caspase-3, caspase-7, PARP apoptotic genes expression downstream of endoplasmic reticulum stress genes (24)(25). We investigate the effect of Zn de ciency on the liver in apoptosis caused from the endoplasmic reticulum stress aspect.…”

Section: Introductionmentioning

confidence: 99%

Zinc Deficiency Induces Endoplasmic Reticulum Stress Leading To Hepatocyte Apoptosis in Mice

Cui

Wang

Deng

et al. 2022

Preprint

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Zinc (Zn) is a crucial trace element for the organism. We investigated Zn deficiency causing endoplasmic reticulum stress and apoptosis by establishing a mouse Zn deficiency model (34 mg/kg in CG group and 2 mg/kg in LG group) and hepatocyte Zn deficiency model (add 0 umol TPEN in CCG group, add 50 umol TPEN in C50 group, add 100 umol TPEN in C100 group). The Zn deficiency caused oxidative stress and produced a large amount of ROS, which had a greater effect on the endoplasmic reticulum and caused endoplasmic reticulum stress. HE staining, liver tissue showed more inflammatory cell infiltration, and TUNEL showed that more apoptotic cells appeared in the LG group compared with the CG group. In RT-PCR assay, we found that the expression of GRP78, IRE-1α, ATF6, PERK, and Chop gene increased in the Zn deficiency group, and caspase-12, caspase-9, caspase-3, caspase-7, PARP apoptotic gene expression were increased. In the apoptosis assay, AO/EB staining clearly showed an increase in apoptotic cells in the Zn-deficient group. Our study provides some basis for the effects of trace element Zn on the liver in terms of endoplasmic reticulum stress.

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Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress

Cited by 8 publications

References 34 publications

Potential Theranostic Roles of SLC4 Molecules in Human Diseases

Potential Theranostic Roles of SLC4 Molecules in Human Diseases

Characterization of a novel mouse model for Fuchs Endothelial Corneal Dystrophy

Zinc Deficiency Induces Endoplasmic Reticulum Stress Leading To Hepatocyte Apoptosis in Mice

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