Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

Hou, Shu; Wang, Lili; Zhang, Guoping

doi:10.1007/s12576-019-00685-6

Cited by 16 publications

(10 citation statements)

References 67 publications

(72 reference statements)

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“…Moreover, Mfn2-UPR interaction plays an important regulatory role in inflammation response. For instance, overexpression of Mfn2 alleviated TNFα-mediated ER stress in N2a cells by suppressing the expression of CHOP, caspase3, and caspase12 ( Hou et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Cao¹,

Chen²,

Hu³

et al. 2021

Front. Cell Dev. Biol.

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The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

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Section: Discussionmentioning

confidence: 99%

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Cao¹,

Chen²,

Hu³

et al. 2021

Front. Cell Dev. Biol.

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“…(Xin et al, 2019). Moreover, in mouse neuroblastoma N2a cells, mfn2 can affect ER stress through Yap-Hippo pathway (Hou et al, 2019). These evidences suggest that mfn2 is involved in regulating the function of the ER.…”

Section: Mitochondrial Dysfunction Impairs Follicular Developmentmentioning

confidence: 90%

Mitochondrial Dysfunction in Polycystic Ovary Syndrome

Zeng

Huang

Long

et al. 2020

DNA and Cell Biology

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Polycystic ovary syndrome (PCOS) is one of the most common female reproductive metabolisms. It is an endocrine disease that affects reproductive women and often exhibits with hyperandrogenemia, insulin resistance (IR), low inflammation, and an increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular events such as hypertension and dyslipidemia in patients. However, the molecular mechanism of PCOS is still unclear. Recently, an increasing number of studies have shown that the oxidative stress induced by mitochondrial dysfunction has negative effects on IR, lipid metabolism, and follicular development, suggesting that mitochondrial dysfunction plays an essential role in the development of PCOS. Abnormal mitochondrial DNA copy number in patients with PCOS, and mitochondrial gene mutations, has been the focus of research in recent years, and functional mitochondrial diseases have been gradually accepted as a related factor in PCOS. This review is intended to summarize and discuss previous and recent studies and findings on the connections between mitochondrial dysfunction and PCOS.

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“…Moreover, inflammation-induced ER stress is also involved in neurotoxicity. It has been proven that inhibiting ER stress attenuates inflammation-mediated neuronal dysfunction, and this effect ultimately decreases the expression of apoptosis-associated proteins in the inflammatory microenvironment [ 61 ]. Taken together, these results suggest that ER stress and inflammation are highly orchestrated processes.…”

Section: Discussionmentioning

confidence: 99%

TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease

Liu

Bai

et al. 2022

J Neuroinflammation

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Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Its molecular mechanism is still unclear, and pharmacological treatments are unsatisfactory. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+ channel. It has recently emerged as a critical risk factor in the pathophysiology of neuronal injuries and cerebral diseases. Our previous study reported that TRPV4 contributed to endoplasmic reticulum (ER) stress in the MPP+-induced cell model of PD. In the present study, we detected the role and the mechanism of TRPV4 in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Methods Intracerebral injection of an adeno-associated virus (AAV) into the substantia nigra (SN) of mice was used to knockdown or upregulate the expression of TRPV4 and intraperitoneal injection of MPTP. Rotarod and pole tests were used to evaluate the locomotor ability of mice. We used immunohistochemistry, Nissl staining and Western blot to detect the alterations in the number of tyrosine hydroxylase (TH)-positive neurons, Nissl-positive neurons, the levels of ER stress-associated molecules and proinflammatory cytokines in the SN. Results The SN was transfected with AAV for 3 weeks and expressed the target protein with green fluorescence. Knockdown of TRPV4 via injection of a constructed AAV-TRPV4 shRNAi into the SN alleviated the movement deficits of PD mice. Upregulation of TRPV4 via injection of a constructed AAV-TRPV4 aggravated the above movement disorders. The expression of TRPV4 was upregulated in the SN of MPTP-treated mice. Injection of AAV-TRPV4 shRNAi into the SN rescued the number of TH-positive and Nissl-positive neurons in the SN decreased by MPTP, while injection of AAV-TRPV4 induced the opposite effect. Moreover, MPTP-decreased Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and pro-cysteinyl aspartate specific proteinase-12 (procaspase-12), MPTP-increased Glucose-regulated protein 78 (GRP78), Glucose-regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP) were inhibited by AAV-TRPV4 shRNAi infection, and enhanced by AAV-TRPV4. In the same way, MPTP-decreased procaspase-1, MPTP-increased Interleukin-18 (IL-18), Cyclooxgenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) were inhibited by AAV-TRPV4 shRNAi, or further exacerbated by AAV-TRPV4. Conclusions These results suggest that TRPV4 mediates ER stress and inflammation pathways, contributing to the loss of dopamine (DA) neurons in the SN and movement deficits in PD mice. Moreover, this study provides a new perspective on molecular targets and gene therapies for the treatment of PD in the future.

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Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

Cited by 16 publications

References 67 publications

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

Mitochondrial Dysfunction in Polycystic Ovary Syndrome

TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease

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