Alterations in mitochondrial dynamics with age‐related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Zhang, Jingwen; He, Zhibin; Fedorova, Julia; Logan, Cole; Bates, Lauryn; Davitt, Kayla; Le, Van; Murphy, Jiayuan; Li, Melissa; Wang, Mingyi; Lakatta, Edward G.; Ren, Di; Li, Ji

doi:10.1111/acel.13419

Cited by 48 publications

(39 citation statements)

References 44 publications

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“…Western blot analysis and co‐immunoprecipitation (co‐IP) were performed following previous description with some modification (Bourdenx et al, 2021; Shen et al, 2021; Zhang et al, 2021). We performed plasma membrane protein isolation according to the directions provided by Minute™ Plasma Membrane Protein Isolation and Cell Fractionation Kit (Invent Biotechnologies, catalog number: SM‐005).…”

Section: Methodsmentioning

confidence: 99%

Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β‐amyloid load in Alzheimer's disease model

Shen

Zhang

et al. 2022

Aging Cell

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Inducing gamma oscillations with non‐invasive light flicker has been reported to impact Alzheimer's disease‐related pathology. However, it is unclear which signaling pathways are involved in reducing amyloid load. Here, we found that gamma frequency light flicker increased anchoring of amyloid precursor protein (APP) to the plasma membrane for non‐amyloidogenic processing, and then physically interacted with KCC2, a neuron‐specific K+‐Cl− cotransporter, suggesting that it is essential to maintain surface GABAA receptor α1 levels and reduce β‐amyloid (Aβ) production. Stimulation with such light flicker limited KCC2 internalization and subsequent degradation via both tyrosine phosphorylation and ubiquitination, leading to an increase in surface‐KCC2 levels. Specifically, PKC‐dependent phosphorylation of APP on a serine residue was induced by gamma frequency light flicker, which was responsible for maintaining plasma membrane levels of full‐length APP, leading to its reduced trafficking to endosomes and inhibiting the β‐secretase cleavage pathway. The activated PKC from the gamma frequency light flicker subsequently phosphorylated serine of KCC2 and stabilized it onto the cell surface, which contributed to the upregulation of surface GABAA receptor α1 levels. Together, these data indicate that enhancement of APP trafficking to the plasma membrane via light flicker plays a critical modulatory role in reduction of Aβ load in Alzheimer's disease.

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Section: Methodsmentioning

confidence: 99%

Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β‐amyloid load in Alzheimer's disease model

Shen

Zhang

et al. 2022

Aging Cell

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“…[ 35 ] For example, age‐related deficiency of SIRT3 in heart was proven to affect mitochondrial function, resulting in impaired contractile function of cardiomyocytes. [ 36 ] Here, we found that AR‐C17 could enhance SIRT3 expression in a dose‐dependent manner both in ApoE −/− mice and ox‐LDL‐treated HUVECs. Moreover, the protective effect of AR‐C17 on cells apoptosis, mitochondrial dynamic, and respiration function was depended on SIRT3, indicating it maybe a specific target signaling molecule of AR‐C17.…”

Section: Discussionmentioning

confidence: 77%

5‐Heptadecylresorcinol Protects against Atherosclerosis in Apolipoprotein E‐Deficient Mice by Modulating SIRT3 Signaling: The Possible Beneficial Effects of Whole Grain Consumption

Hao

Yang

et al. 2022

Molecular Nutrition Food Res

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Scope Whole grain consumption has been proven to be inversely associated with the risk of cardiovascular diseases. As a biomarker for whole grain dietary intake, 5‐heptadecylresorcinol (AR‐C17) has attracted increased attention due to its potential health‐improving activity. However, the beneficial effect of AR‐C17 on atherosclerosis prevention and the underlying mechanism remain unclear. Methods and Results High‐fat diet fed apolipoprotein E‐deficient (ApoE−/−) mice are administrated with or without AR‐C17 (30 and 150 mg kg−1) for 16 weeks. Histological staining is performed for plaque analysis. Immunofluorescence, western blot, and seahorse cell analysis are carried out to investigate the action of mechanism of AR‐C17. The results indicate that AR‐C17 supplementation lowered serum total cholesterol, triglyceride, VLDL‐C, and LDL‐C levels. Moreover, the atherosclerotic plaques in the aortic root region of mice heart are significantly reduced by AR‐C17 intervention compared with ApoE−/− control group. In addition, AR‐C17 treatment alleviates endothelial cell damage and apoptosis by improving mitochondrial function via sirtuin3 signaling pathway both in ApoE−/− mice and oxidized‐LDL‐treated human umbilical vein endothelial cells. Conclusion AR‐C17 may be applied as a promising grain‐based dietary bioactive ingredient for atherosclerosis prevention. Meanwhile, as a mitochondrial protective agent, it can offer support for the suggested health claim of whole grain diet.

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“…In addition, the activation of SIRT1 and SIRT3 could activate the ATP production and the mitochondrial antioxidant function in skeletal muscle 37 . Furthermore, it was reported that SIRT1/SIRT3 deficiency resulted in impaired mitochondrial fusion and decreased mitochondrial perimeter in cardiomyocyte 38 . More importantly, as previously reported, the deficiency of SIRT1/3 have identified to promote the progression of PAH 17 , 18 .…”

Section: Discussionmentioning

confidence: 99%

The MFF-SIRT1/3 axis, regulated by miR-340-5p, restores mitochondrial homeostasis of hypoxia-induced pulmonary artery smooth muscle cells

Jiang

Zhang

et al. 2022

Laboratory Investigation

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Mitochondrial dynamics and quality control play a central role in the maintenance of the proliferation–apoptosis balance, which is closely related to the progression of pulmonary arterial hypertension (PAH). However, the exact mechanism of this balance remains unknown. Pulmonary artery smooth muscle cells (PASMCs) were cultured in hypoxia condition for constructing a PAH model in vitro. The expression of genes and proteins were determined by qRT-PCR and western bolt assays. Cell proliferation–apoptosis balance were tested by MTT, EdU and TUNEL assays. The mitochondrial functions were assessed by flow cytometry, JC-1, Mito tracker red staining, and corresponding kits. Besides, the molecular interaction was validated by dual-luciferase reporter assay. MFF was overexpressed in hypoxia-treated PAMSCs. Knockdown of MFF significantly repressed the excessive proliferation but enhanced cell apoptosis in hypoxia-treated PAMSCs. Moreover, MFF silencing improved mitochondrial function of hypoxia-treated PAMSCs by increasing ATP production and decreasing ROS release and mitochondrial fission. Mechanistically, MFF was a directly target of miR-340-5p, and could negatively regulate SIRT1/3 expression. Subsequently, functional rescue assays showed that the biological effects of MFF in hypoxia-treated PAMSCs were negatively regulated by miR-340-5p and depended on the regulation on SIRT1/3 pathway. These results provided evidences that miR-340-5p regulated MFF-SIRT1/3 axis to improve mitochondrial homeostasis and proliferation–apoptosis imbalance of hypoxia-treated PAMSCs, which provided a theoretical basis for the prevention and treatment of PAH.

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Alterations in mitochondrial dynamics with age‐related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 48 publications

References 44 publications

Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β‐amyloid load in Alzheimer's disease model

Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β‐amyloid load in Alzheimer's disease model

5‐Heptadecylresorcinol Protects against Atherosclerosis in Apolipoprotein E‐Deficient Mice by Modulating SIRT3 Signaling: The Possible Beneficial Effects of Whole Grain Consumption

The MFF-SIRT1/3 axis, regulated by miR-340-5p, restores mitochondrial homeostasis of hypoxia-induced pulmonary artery smooth muscle cells

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