Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications

Mills, Emily M.; Barlow, Victoria L.; Luk, Louis Y. P.; Tsai, Yu‐Hsuan

doi:10.1007/s10565-019-09488-2

Cited by 9 publications

(6 citation statements)

References 105 publications

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“…Cells were grown in clear-bottom 96-well black plates (Corning Inc.) and then incubated in the presence or absence of Mfn2 small interfering RNA (siRNA) for 48 h at 37 • C. Then, the cells were washed with phosphate-buffered saline (pH 7.4) and further incubated with MitoSOX red mitochondrial superoxide indicator (Molecular Probes, Eugene, OR, United States) for 18 h at 37 • C (Bakhta et al, 2020). Subsequently, the cells were washed twice with phosphate-buffered saline (pH 7.4) and the fluorescence of MitoSOX was read at excitation/emission wavelengths of 485/530 nm (Islam, 2020;Mills et al, 2020).…”

Section: Measurement Of Mitochondrial Ros Productionmentioning

confidence: 99%

RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy

Zhang

Wang

2021

Front. Physiol.

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Diabetic cardiomyopathy has been associated with mitochondrial damage. Mitochondria–endoplasmic reticulum (ER) contact is an important determinant of mitochondrial function and ER homeostasis. We therefore investigated whether hyperglycemia can damage the mitochondria by increasing their contact with the ER in cardiomyocytes. We found that hyperglycemia induced mitochondria–ER contact in cardiomyocytes, as evidenced by the increased MMM1, MDM34, and BAP31 expressions. Interestingly, the silencing of Mfn2 reduced the cooperation between the mitochondria and the ER in cardiomyocytes. Mfn2 silencing improved cardiomyocyte viability and function under hyperglycemic conditions. Additionally, the silencing of Mfn2 markedly attenuated the release of calcium from the ER to the mitochondria, thereby preserving mitochondrial metabolism in cardiomyocytes under hyperglycemic conditions. Mfn2 silencing reduced mitochondrial reactive oxygen species production, which reduced mitochondria-dependent apoptosis in hyperglycemia-treated cardiomyocytes. Finally, Mfn2 silencing attenuated ER stress in cardiomyocytes subjected to high-glucose stress. These results demonstrate that Mfn2 promotes mitochondria–ER contact in hyperglycemia-treated cardiomyocytes. The silencing of Mfn2 sustained mitochondrial function, suppressed mitochondrial calcium overload, prevented mitochondrial apoptosis, and reduced ER stress, thereby enhancing cardiomyocyte survival under hyperglycemic conditions.

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Section: Measurement Of Mitochondrial Ros Productionmentioning

confidence: 99%

RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy

Zhang

Wang

2021

Front. Physiol.

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“…Endoplasmic reticulum (ER) facilitates the processing of newly formed prosurvival and proproliferation proteins required for tumor growth and metastasis. Impaired ER activity or ER stress has been shown to contribute to thyroid carcinoma metastasis [ 5 , 6 ]. Another study reported that ER stress reduced the radiosensitivity of thyroid carcinoma cells and inhibited apoptosis [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis

Zhang

Han

et al. 2021

Journal of Oncology

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Although the incidence of thyroid carcinoma has increased over the past several decades, it has an excellent prognosis and overall 5-year survival, with a stable mortality rate, except in cases with advanced stages or rare malignant tumor types. Biomarkers have emerged as effective targets of molecular therapy against thyroid carcinoma due to their rapid and convenient detection; however, there has been little clinical application. Macrophage stimulating 2 (Mst2) is a proapoptotic protein with implications in carcinogenesis and metastasis. We found that Mst2 overexpression-induced endoplasmic reticulum (ER) stress in MDA-T32 thyroid carcinoma cells, accompanied by elevated caspase-12 activity, increased apoptotic rate, and reduced cell viability. In addition, Mst2 overexpression contributed to mitochondrial damage, as evidenced by increased mitochondrial oxidative stress and activated the mitochondrial apoptotic pathway. Inhibition of the JNK pathway abolished these effects. These results show Mst2 to be a novel tumor suppressor that induces mitochondrial dysfunction and ER stress via the JNK pathway. Thus, Mst2 could potentially serve as a biomarker for developing targeted therapy against thyroid carcinoma.

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“…The protective mechanism afforded by Opa1mediated mitophagy involves inhibition of mitochondrial fission and activation of the MAPK/ERK pathway. The protective role of mitophagy on mitochondrial homeostasis and cardiomyocyte viability has been widely reported [63][64][65]. For example, irisin treatment significantly activates Opa1mediated mitophagy and thus inhibits cardiomyocyte mitochondrial apoptosis following myocardial infarction [66][67][68].…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Optic Atrophy 1 on Cardiomyocyte Oxidative Stress: Roles of Mitophagy, Mitochondrial Fission, and MAPK/ERK Signaling

Wang

Han

et al. 2021

Oxidative Medicine and Cellular Longevity

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Myocardial infarction is associated with oxidative stress and mitochondrial damage. However, the regulatory mechanisms underlying cardiomyocyte oxidative stress during myocardial infarction are not fully understood. In the present study, we explored the cardioprotective action of optic atrophy 1- (Opa1-) mediated mitochondrial autophagy (mitophagy) in oxidative stress-challenged cardiomyocytes, with a focus on mitochondrial homeostasis and the MAPK/ERK pathway. Our results demonstrated that overexpression of Opa1 in cultured rat H9C2 cardiomyocytes, a procedure that stimulates mitophagy, attenuates oxidative stress and increases cellular antioxidant capacity. Activation of Opa1-mediated mitophagy suppressed cardiomyocyte apoptosis by downregulating Bax, caspase-9, and caspase-12 and upregulating Bcl-2 and c-IAP. Using mitochondrial tracker staining and a reactive oxygen species indicator, our assays showed that Opa1-mediated mitophagy attenuated mitochondrial fission and reduced ROS production in cardiomyocytes. In addition, we found that inhibition of the MAPK/ERK pathway abolished the antioxidant action of Opa1-mediated mitophagy in these cells. Taken together, our data demonstrate that Opa1-mediated mitophagy protects cardiomyocytes against oxidative stress damage through inhibition of mitochondrial fission and activation of MAPK/ERK signaling. These findings reveal a critical role for Opa1 in the modulation of cardiomyocyte redox balance and suggest a potential target for the treatment of myocardial infarction.

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Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications

Cited by 9 publications

References 105 publications

RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy

RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy

Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis

Protective Effect of Optic Atrophy 1 on Cardiomyocyte Oxidative Stress: Roles of Mitophagy, Mitochondrial Fission, and MAPK/ERK Signaling

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