Inﬂammation has been increasingly studied as part of the pathophysiology of neurodegenerative diseases. Mammalian Ste20-like kinase 1 (Mst1), a key factor of the Hippo pathway, is connected to cell death. Unfortunately, little study has been performed to detect the impact of Mst1 in neuroninflammation. The results indicated that Mst1 expression was upregulated because of LPS treatment. However, the loss of Mst1 sustained BV-2 cell viability and promoted cell survival in the presence of LPS treatment. Molecular investigation assay demonstrated that Mst1 deletion was followed by a drop in the levels of mitochondrial fission via repressing Drp1 expression. However, Drp1 adenovirus transfection reduced the protective impacts of Mst1 knockdown on mitochondrial stress and neuronal dysfunction. Finally, our results illuminated that Mst1 affected Drp1 content and mitochondrial fission in a JNK-dependent mechanism. Reactivation of the JNK axis inhibited Mst1 knockdown-mediated neuronal protection and mitochondrial homeostasis. Altogether, our results indicated that Mst1 upregulation and the activation of JNK-Drp1-mitochondrial fission pathway could be considered as the novel mechanism regulating the progression of neuroninflammation. This finding would pave a new road for the treatment of neurodegenerative diseases via modulating the Mst1-JNK-Drp1-mitochondrial fission axis.

1 INTRODUCTION

Parkinson's disease (PD) is an inflammation-induced central nervous system (CNS) disorder. Although several theories have been proposed to explain the pathogenesis of PD, the inflamamtion-mediated neuronal death has been reported to be the key factor involving PD development and progression. Unfortunately, the detailed molecular basis by which neuroinflammation mediates the neuronal damage has not been fully addressed (Man, Sanchez Duffhues, Ten Dijke, & Baker, 2019).

At the molecular levels, mitochondria have been found to be associated with neuronal dysfunction. Healthy mitochondria constantly produce ATP to ensure neuronal metabolism (Coverstone et al., 2018). Interestingly, under inflammation conditions, mitochondria are the potential target and undergo abnormal mitochondrial fission to transmit the inflammatory signals to cells (Erland, Yasunaga, Li, Murch, & Saxena, 2018). For example, in inflammation-treated alveolar epithelial cells, mitochondrial fission is induced in the LPS-mediated inflammation microenvironment and is responsible for the cell damage (Bittremieux et al., 2019). Besides, in LPS-treated microglial cells, Drp1-induced mitochondrial dynamics disorder modulates p62-required autophagy and this effect is connected to cell damage as well as mitochondrial dysfunction (Chandra et al., 2018). Besides, in BV2 neuronal cells, oxygen glucose deprivation-induced inflammation augments neuronal energy disorder and dysfunction via controlling TLR4/Myd88/Drp1-related mitochondrial fission (Zhou, Wang et al., 2018). The above information indicates that inflammation-mediated neuronal dysfunction seems to be regulated by mitochondrial fission, which contributes mitochondrial stress and neuronal death via multiple effects (Zhang, Jin, & Faber, 2019). However, the molecular affecting the mitochondrial fission has been not explored in inflammation-modulated neuronal damage.

Mammalian Ste20-like kinase 1 (Mst1), a key factor of the Hippo pathway, is handled by inflammation damage (Dickinson et al., 2018). For example, in LPS-induced hepatocyte damage, Mst1 is activated and augments the mitochondrial damage via reducing mitochondrial membrane potential and augmenting caspase activation (Merz et al., 2018). Besides, Mst1 also modulates post-infarction myocardial damage through controlling the JNK-Drp1 pathway. The impacts of Mst1-Hippo on mitochondrial dynamics have also been validated in liver cancer, hyperglycemia-attacked retinal pigmented epithelial cells, and renal ischemia-reperfusion injury. Herein, we conducted cellular assay to explore whether Mst1 is connected to mitochondrial fission under neuroinflammation (Wei et al., 2018).

Mechanistically, fission is post-transcriptionally handled by a key mitochondrial fission factor and that is Drp1 (Saito et al., 2019). Drp1 activation and translocation from cytoplasm onto the outer membrane of mitochondria seem to be a key upstream event. During this process, activated JNK could indirectly and/or directly elevate the transcription and/or expression of Drp1, amplifying Drp1-dependent mitochondrial fission (Zhou, Zhu et al., 2018). Accordingly, JNK protein is thought as to be the critical controlled in the processes of Drp1-mediated fission and JNK's action is validated by several studies including rectal cancer cells, cardiac reperfusion injury, and endometrial stromal cells (Zhu, Jin et al., 2018). Herein, we conducted cellular assays to understand whether inflammation-activated Drp1 fission is modulated by the JNK pathway.

2 MATERIALS AND METHODS

2.1 Cell line and inflammation model

Murine microgalia BV2 were cultured with Dulbecco's modified Eagle's medium (DMEM; Gibco, Carlsbad, CA) containing 10% fetal bovine serum (FBS; Hyclone, Logan, UT), 2 mM glutamine, and 200 mM streptomycin/penicillin and maintained in 5% CO₂ at 37°C. These cells were cultured with LPS (10 μg/ml) for 12 hr according to a recent report (Sajib, Zahra, Lionakis, German, & Mikelis, 2018).

2.2 MTT assay and TUNEL staining

Approximately, 8 × 104 cells in logarithmic growth were seeded in a 96-well culture plate. Twenty microliters of MTT solution (5 mg/ml) was added to each well, and then the cells were cultured for 4–6 hr. After removal of the supernatant, 150 μl of dimethyl sulfoxide was added. The 96-well culture plate was shaken for 10 min till crystal was completely dissolved. The optical density of dimethyl sulfoxide at 570 nm was measured on a plate reader. Cell survival rate was calculated as follows: (OD sample − OD sample blank) / (OD control − OD control blank) × 100%(Mehra et al., 2018). After treatment with LPS, the samples were stained with 50 μl of TUNEL reaction mixture. After washing with PBS, the samples were scanned by a confocal microscope (TCS SP5, Leica) at room temperature (Magni et al., 2019).

2.3 ROS flow cytometry analysis

After treatment with LPS, samples were harvested using enzyme digestion and prepared as a single-cell suspension. Subsequently, the single-cell suspension was stained with mROS probe (Molecular Probes) for 15 min at room temperature_. Then, the single-cell suspension was washed with PBS, and FACSCaliber flow cytometry was applied to quantify the content of mROS. The relative content of mROS was measured by recording the percentages of positive and negative cells (Mantovani, Collavin, & Del Sal, 2019).

2.4 Enzyme-linked immunosorbent assay

The levels of cellular antioxidants, including SOD, GSH, and GPX, were analyzed through enzyme-linked immunosorbent assay (ELISA) kits. In addition, LDH content, caspase-3/9 activities were analyzed through ELISA kits (R&D Systems, Abingdon, UK) on the basis of a recent report (Shen et al., 2018).

2.5 mPTP opening detection and mitochondrial membrane potential observation

The mitochondrial potential was observed through the JC-1 probe (Beyotime, China, Cat. No:C2006). mPTP opening was evaluated according to a previous study using tetramethylrhodamine ethyl ester (Renn et al., 2018). The relative mPTP opening was measured as a ratio to that of the control group (Sinha et al., 2018).

2.6 RNA interference and transfection

BV-2 cells were transfected with Mst1-siRNA (5′-GATTAGCAGCCAGTGTCTTAG-3′) and negative control (si-RNA) (5′-TTACCGAGACCGTACGTAT-3′) synthesized by GenePharma (Shanghai, China), and were selected in DMEM containing 2 μg/ml puromycin. The pcDNA3.1-Drp1 were bought from Cyagen Company (Cyagen Biosciences Inc., Guangzhou, China; Masaldan et al., 2018), and the cells in the six-well plate were transfected 2 μg plasmid using Lipofectamine 2000 reagent, and complete medium was added after 6 hr transfection (Oh & Mouradian, 2018).

2.7 Western blot analysis

2.7.1 Western blot assay

Whole protein was extracted from whole cell lysate using RIPA buffer and the concentration was measured using a BCA assay. The protein (30 μg) was separated by 12.5% SDS-PAGE. Proteins were transferred to PVDF membranes (EMD Millipore, Billerica, MA) at 300 mA for 90 min. The membranes were then blocked at room temperature for 1 hr with TBST containing 0.1% Tween-20% and 5% dry milk and incubated overnight with primary antibodies at 4°C (Paul, Gangwar, Bhargava, & Ahmad, 2018). Membranes were washed in triplicate with TBST and incubated for 2 hr with secondary antibodies at room temperature. The western blot was performed using a Luminescent Image Analyzer (Protein Simple, San Jose, CA; Jeelani et al., 2018), and the optical densities of antibody-specific bands were analyzed using the ImageJ software (Version 1.37 for Windows, National Institutes of Health, Bethesda, MD). The optical densities of antibody-specific bands were analyzed using a Luminescent Image Analyzer (Protein Simple; Serrato, Romero-Puertas, Lazaro-Payo, & Sahrawy, 2018).

2.8 Statistical analysis

Prism 6 (version 6.01, GraphPad Software, Inc., San Diego, CA) was used for data analysis. Results in our study were shown as mean ± standard deviation (SD) of at least three independent experiments (Fan et al. (2018). Differences between multiple groups were analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni post hoc. p < .05 was considered statistically significant.

3 RESULTS

3.1 Inflammation-activated Mst1 promotes BV-2 cell death

First, LPS was used to mimic the inflammation damage in BV-2 cells. Then, the protein analysis was used to detect the content of Mst1 under inflammation damage. In Figure 1a,b, LPS treatment elevated the transcription and expression of Mst1 in BV-2 cells. To figure out the action exerted by Mst1 in inflammation-mediated BV-2 cell damage (Kiel, Goodwill, Baker, Dick, & Tune, 2018), Mst1 siRNA against was used to silence inflammation-mediated Mst1 upregulation and the protein knockdown was observed through western blot analysis (Figure 1a,b). After the loss of Mst1, cell viability, as determined through the MTT assay, was reversed to near-normal levels under LPS treatment (Figure 1c). These data were further validated by analyzing the released LDH content in the medium induced by LPS. In Figure 1d, LPS treatment promoted BV-2 cells release LDH in the medium, indicative of cell membrane breakage because of LPS stress. However, Mst1 knockdown inhibited the LDH release, suggestive of the pro-survival effect exerted by Mst1 deletion in LPS-treated BV-2 cells. Moreover, the TUNEL assay was applied to further analyze the cell survival rate. In Figure 1e,f, LPS upregulated the ratio of TUNEL-positive cells whereas Mst1 knockdown reduced cell death in BV-2 cells. To observe whether death is proceeded by apoptosis, caspase-3 expression and activity were measured. In Figure 1g,h, the expression of cleaved caspase-3 was downregulated by LPS treatment (Higgs et al., 2019). In addition to capsase-3 cleavage, the content of cleaved PARP was also increased after exposure to LPS stress, reconfirming the activation of caspase-3 by LPS treatment. Interestingly, Mst1 knockdown repressed the content of cleaved caspase-3 and PARP. In addition to the protein's expression, we also found that the caspase-3 activity was augmented due to LPS stress (Figure 1i), this action could be reversed by Mst1 knockdown. Altogether, the above data indicate the critical action played by Mst1 in augmenting LPS-mediated neuronal death in BV-2 cell in vitro.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Mst1 deletion attenuates LPS-mediated cell death in BV-2 cells. (a,b) Proteins were isolated from BV-2 cells and then the expression of Mst1 was evaluated via western blots. siRNA against Mst1 was transfected into BV-2 cells. (c) Cell viability was determined via the MTT assay. Mst1 siRNA was transfected into BV-2 cells. (d) LDH release assay was used to detect cell death in response to LPS treatment and/or Mst1 deletion.(e,f) Cell death was determined via TUNEL staining. The number of apoptotic cells were recorded. (g,h) Proteins were isolated from BV-2 cells and then the expression of apoptotic proteins was evaluated via western blots. siRNA against Mst1 was transfected into BV-2 cells. (i) The caspase-3 activity was determined via ELISA. siRNA against Mst1 was transfected into BV-2 cells. Mst1, mammalian Ste20-like kinase 1. *p < .05 vs. control group; #p < .05 vs. LPS + si-ctrl group [Color figure can be viewed at wileyonlinelibrary.com]

3.2 Loss of Mst1 reverses mitochondrial function in the inflammation microenvironment

Mitochondrial damage has been found to be closely associated with neuronal dysfunction via impairing energy supply and activating apoptosis (Montoya-Zegarra et al., 2019). Accordingly, a mitochondrial functional abnormality was detected under LPS-related inflammation stress. In Figure 2a, ATP production was downregulated in BV-2 cell after exposure to LPS. Interestingly, Mst1 knockdown reversed ATP production in BV-2 cells. In addition to energy metabolism, we also found that mitochondrial oxidative stress, as evaluated via observing mitochondrial ROS production through flow cytometry, was elevated due to LPS stress and was reversed to near-normal levels with Mst1 knockdown (Figure 2b). This result suggests mitochondrial dysfunction is modulated by LPS via Mst1 upregulation. Excessive mitochondrial dysfunction would activate mitochondrial apoptosis, as featured by cyt-c release, mPTP opening, and caspase-9 activation. Through immunofluorescence, we found that the nuclear levels of cyt-c were augmented by LPS-related inflammation stress whereas Mst1 knockdown inhibited the rise in the nuclear cyc-t (Figure 2c,d). In addition to cyt-c release, the mPTP opening rate was also positively affected by LPS and was preserved by Mst1 silencing (Figure 2e). Finally, western blots were applied to detect the changes in mitochondria-related apoptotic proteins. In Figure 2f-i, the levels of caspase-9 and Bax were boosted by LPS while the expression of Bcl-2 was downregulated (Li, Cai, et al., 2018). Interestingly, Mst1 knockdown reversed the levels of mitochondrial antiapoptotic factors and inhibited caspase-9/Bax. Herein, this information illuminates that mitochondria function is protected by Mst1 deficiency under LPS stress.

3.3 Mst1 activation promotes mitochondrial fission via Drp1

Mitochondrial function and apoptosis have been reported to be governed by mitochondrial fission (Nwadozi et al., 2019). Through analyzing mitochondrial morphology by immunofluorescence (Na et al., 2019), we found that mitochondria were strip and this morphology was converted into fragmentation once treatment with LPS. Interestingly, Mst1 knockdown reversed the mitochondrial network. Previous studies have used the average length of mitochondria to quantify fission. In Figure 3a, the average length of mitochondria was ~9.2 μm under normal conditions (Meyer & Leuschner, 2018). Interestingly, LPS treatment reduced mitochondrial length to~4.2 μm and this parameter was reversed to~8.7 μm after the loss of Mst1. This result indicates that fission is positively affected through LPS due to Mst1 upregulation. Subsequently, protein analysis was used to detect the molecular mechanism underlying LPS-related fission. In Figure 3b-f, LPS upregulated the content of Drp1/Mff, the key factors belonging to pro-fission components. However, Mfn2/ Opa1 were rapidly downregulated by LPS treatment. Mfn2/Opa1 were the key anti-fission factors that correct excessive mitochondrial fission. Interestingly, Mst1 knockdown repressed the levels of Drp1/Mff whereas reversed the content of Mfn2/Opa1. Altogether, the above results illustrate that loss of Mst1 could abolish the mitochondrial fission induced by LPS.

3.4 Inhibition of Drp1 abolishes Mst1-induced mitochondrial damage and cell death

Although we found that Drp1-associated fission has been triggered by Mst1 in BV-2 cells, little was known about its role in mitochondrial damage and cell death (Kim et al., 2019). Subsequently, Drp1 adenovirus (ad-Drp1) was transfected into Mst1-silenced cells and mitochondrial function, as well as cell viability, were measured again. As shown in Figure 4a,b, ad-Drp1 significantly elevated the expression of Drp1 in Mst1-deleted cells. Interestingly, cell viability, as assessed via MTT assay, was significantly repressed by ad-Drp1 transfection, when compared with the Mst1-deleted cells (Figure 4c). Besides, the caspase-3 activity, a hallmarker of cellular death, was significantly inactivated by Mst1 silencing in LPS-treated cells (Figure 4d) whereas ad-Drp1 infection-mediated Drp1 overexpression abolished the pro-survival effect of Mst1 silencing. Therefore, these results indicated that Mst1 deletion-mediated cell protection was abolished by Drp1 overexpression. With respect to mitochondrial damage, cyt-c immunofluorescence demonstrated that Mst1 deletion could prevent LPS-mediated cyt-c nucleus migration (Figure 4e,f). However, after Drp1 overexpression via transfecting ad-Drp1 could significantly abolish the inhibitory effects of Mst1 deletion on cyt-c release. Besides, ATP synthesis was maintained by Mst1 silencing because of LPS stress (Figure 4g). Interestingly, Drp1 overexpression repressed ATP generation in Mst1-deleted cells, indicating that Mst1 modulated cellular energy metabolism via Drp1-associated fission. In addition, the caspase-9 activity was boosted by LPS treatment whereas this alteration was abolished because of Mst1 silencing (Figure 4h). However, the caspase-9 activity was re-activated by Drp1 reintroduction induced by ad-Drp1 infection. Herein, our data illuminate that Drp1-associated fission is involved in Mst1-related mitochondrial stress and cell death.

3.5 Mst1 regulates Drp1-related fission through the JNK axis

Finally, experiments were further conducted to explain how Mst1 affected Drp1-associated fission. The JNK axis has been reported to be a key signaling pathway regulating Drp1-associated fission (Reddy et al., 2018). Protein analysis illuminated that p-JNK expression was elevated through LPS treatment, indicative of JNK activation. Interestingly, Mst1 deletion could reduce the content of p-JNK (Figure 5a-c; Kiel et al., 2018). To demonstrate whether the JNK pathway was required for Drp1-related mitochondrial fission, pathway agonist (Anisomycin, Ani) was applied in the Mst1-deleted cells (Figure 5a-c). Ani treatment reversed the levels of p-JNK and inhibited the content of Drp1, indicative of Mst1 attenuated Drp1 expression via the JNK pathway. To further analyze whether fission is positively controlled by Mst1 via JNK axis, co-immunofluorescence was used. In Figure 5d,e, LPS enhanced the fluorescence intensity of Drp1, leading to a drop in the average length of mitochondria. Interestingly, Mst1 knockdown inhibited Drp1 expression and maintained mitochondrial length; these actions were ineffective after treatment with Ani. Thus, our data indicate that Drp1-associated fission was controlled by Mst1 via the JNK axis (Giatsidis et al., 2018).

3.6 Blockade of JNK pathway promotes cell survival and maintains mitochondrial homeostasis

Finally, we asked whether the JNK axis was implicated into Mst1-induced mitochondrial damage and cell death (Staudacher et al., 2018). In Figure 6a, LDH release was augmented by LPS treatment whereas Mst1 silencing inhibited LPS-mediated LDH release. Interestingly, activation of JNK pathway could re-caused LDH release in Mst1-deleted cells. These data were further validated through analyzing cell death rate using TUNEL assay (Hobson et al., 2018). In Figure 6b,c, the number of TUNEL-positive cells was elevated by LPS and was suppressed because of Mst1 silencing. Interestingly, JNK activation abolished the antiapoptotic action exerted by Mst1 silencing in BV-2 cells, as evidenced by the increased number of TUNEL⁺ cells. Therefore, our data suggest a necessary action exerted by the JNK axis in controlling the Mst1-induced cell death. With respect to mitochondrial damage, cell oxidative stress, and the caspase-9 activity were evaluated (Fernandez Vazquez, Reiter, & Agil, 2018). In Figure 6d-f, the levels of antioxidant were downregulated by LPS treatment. However, Mst1 silencing restored the content of antioxidants in BV-2 cells, and this action was ineffective because of JNK activation (Serrato et al., 2018). Besides, the LPS-activated caspase-9 activity could be suppressed through silencing Mst1 (Figure 6g), this action was also abolished through JNK activation. Altogether, the above data illustrated that JNK axis was involved in Mst1-triggered mitochondrial damage and cell death.

4 DISCUSSION

Neuroinflammation has been acknowledged as primary factors for the development of several CNS diseases, such as Alzheimer's Disease and PD. At the molecular levels, moderate inflammation response promotes the tissue repair (Angelova et al., 2018; Zhou, Du et al., 2018). Unfortunately, uncontrolled inflammation seems to be a kind of pathophysiological features of neurodegenerative disease since pro-inflammatory factors would shape a neurotoxic environment that mediates neuronal dysfunction and cell death (Zhou, Li et al., 2018; Zhu et al., 2019). Accordingly, it is critically important to gain a better understanding of the mechanism underlying inflammation-initiated neuronal dysfunction (Bocci et al., 2019; Zhu, Hu et al., 2018). In the current study, Mst1 protein was activated through LPS in BV-2 cells and increased Mst1 was closely associated with BV-2 cell death via activating mitochondrial apoptosis (Cuadrado, Kugler, & Lastres-Becker, 2018; Zhao, Lu et al., 2018). Besides, we found that Mst1 upregulation also promoted mitochondrial fission via upregulating Drp1 and augmenting the JNK pathway (Ter Horst et al., 2018; Zhang, Zou, et al., 2019). These observations collectively indicate that Mst1 critically augments inflammation signals and that loss of Mst1 could be recognized as a critical approach to control the inflammation-triggered neuronal injury (Chrifi et al., 2019; Zhou, Shi et al., 2018).

In fact, neuroinflammation is always seen in both human patients and in animal models of PD. However, the molecular mechanism by which inflammation mediates neuronal damage has not been fully explored (Ba & Boldogh, 2018; Zhao, Wang et al., 2018). Herein, after exposure to LPS-mediated inflammation environment, mitochondrial fission was activated, as characterized by the formation of mitochondrial fragmentation and reduced mitochondrial length (Riehle & Bauersachs, 2018; Zhang, Zhang et al., 2019). Besides, our studies validated a necessary action of Drp1 in initiating mitochondrial fission in the LPS context. Drp1 deficiency sustained mitochondrial function and attenuated LPS-mediated cell death. These data confirm that Drp1-related mitochondrial fission seems to be a potential target of inflammation-mediated neuronal damage (Darden, Payne, Zhao, & Chappell, 2019; Zhang et al., 2016). This observation was in agreement with several previous research. For example, in oxygen glucose deprivation-induced neuroinflammation, neuronal dysfunction, and cell death are highly regulated by the TLR4/Myd88/Drp1-related mitochondrial fission. In metabolic syndrome-mediated neuroinflammation, mitochondrial fission is activated by Sirt3 downregulation (Li, Xin et al., 2018; Zhang, Jin et al., 2019). In manganese-treated astrocytes, neuroinflammation is also handled by mitochondrial fission. On the basis of this information, modulation of mitochondrial fission is vital to sustain neuronal viability.

Mst1, a key factor of Hipoo-pathway, is closely associated with the cell death via modulating the stability of Bcl-2 (Abukar et al., 2018; Yao et al., 2019). Recent studies have found a link between Mst1 and brain damage. For example, Mst1/Hippo pathway dysregulation has been noted in human Huntington's disease. Besides, Mst1 suppression attenuates early brain injury via repressing the NF-κB/MMP9 signaling pathway after subarachnoid hemorrhage in mice. Besides, cerebral reperfusion injury is also controlled by Mst1 (Ding et al., 2018; Zhou, Liu et al., 2018). Interestingly, Mst1 is also the upstream mediator of mitochondrial fission in various disease models. For example, sepsis-triggered myocardial damage is augmented by Mst1 activation and mitochondrial fission initiation. In gastric cancer, Mst1 knockdown promotes cancer survival via modulating AMPK-Sirt3-mitochondrial fission pathway (Shi et al., 2018). In renal ischemia reperfusion injury, Mst1 deletion attenuates kidney oxidative stress via suppressing mitochondrial fission (Zarfati, Avivi, Brenner, Katz, & Aharon, 2019). Herein, we found that Mst1 is involved in inflammation-mediated neuronal dysfunction via activating mitochondrial fission, and this finding was in accordance with the previous conclusions. Besides, we further found that JNK axis was governed by Mst1 and activated mitochondrial fission via upregulating Drp1 at the posttranscription levels (Meyer & Leuschner, 2018). Actually, the role of JNK pathway in mitochondrial fission has been widely discussed. In thyroid cancer tongue cancer, non-small cell lung cancer, and cerebral ischemia reperfusion attack (Anderton et al., 2019), the JNK axis is a key upstream signaling pathway regulating mitochondrial fission activation and augmentation (Erland, Shukla, Singh, Murch, & Saxena, 2018). These findings were in agreement with our results. Therefore, an approach to modulate the activity of JNK to control the mitochondrial fission would provide more benefits for patients with neuroinflammation (Cameron et al., 2018).

Overall, our data offer a novel insight into the mechanism underlying neuroinflammation. Increased Mst1 promotes neuronal dysfunction and cell death via activating Drp1-associated fission through the JNK axis. However, more clinical studies are required to validate our findings in the furture (Jin et al., 2018).

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

AUTHORS CONTRIBUTIONS

H.T. and K.W. conceived the research. M.J., J.T.L., and Y.B.Y. performed the experiments. All authors participated in discussing and revising the manuscript.

AVAILABILITY OF DATA

All data generated or analyzed during this study are included in this published article.

REFERENCES

Abukar, Y., Ramchandra, R., Hood, S. G., McKinley, M. J., Booth, L. C., Yao, S. T., & May, C. N. (2018). Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis. Basic Research in Cardiology, 113(5), 35.
10.1007/s00395-018-0695-9
PubMed Web of Science® Google Scholar
Anderton, H., Bandala-Sanchez, E., Simpson, D. S., Rickard, J. A., Ng, A. P., Di Rago, L., … Feltham, R. (2019). RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development. Cell Death and Differentiation, 26(5), 877–889.
10.1038/s41418-018-0166-8
CAS PubMed Web of Science® Google Scholar
Angelova, P. R., Barilani, M., Lovejoy, C., Dossena, M., Vigano, M., Seresini, A., … Lazzari, L. (2018). Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation. Redox Biology, 14, 474–484.
10.1016/j.redox.2017.10.016
CAS PubMed Web of Science® Google Scholar
Ba, X., & Boldogh, I. (2018). 8-Oxoguanine DNA glycosylase 1: Beyond repair of the oxidatively modified base lesions. Redox Biology, 14, 669–678.
10.1016/j.redox.2017.11.008
CAS PubMed Web of Science® Google Scholar
Bittremieux, M., La Rovere, R. M., Akl, H., Martines, C., Welkenhuyzen, K., Dubron, K., … Bultynck, G. (2019). Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2. Cell Death and Differentiation, 26(3), 531–547.
10.1038/s41418-018-0142-3
CAS PubMed Web of Science® Google Scholar
Bocci, M., Sjolund, J., Kurzejamska, E., Lindgren, D., Marzouka, N. A., Bartoschek, M., … Pietras, K. (2019). Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer. Angiogenesis, 22(1), 117–131.
10.1007/s10456-018-9642-5
CAS PubMed Web of Science® Google Scholar
Cameron, A. R., Logie, L., Patel, K., Erhardt, S., Bacon, S., Middleton, P., … Rena, G. (2018). Metformin selectively targets redox control of complex I energy transduction. Redox Biology, 14, 187–197.
10.1016/j.redox.2017.08.018
CAS PubMed Web of Science® Google Scholar
Chandra, M., Escalante-Alcalde, D., Bhuiyan, M. S., Orr, A. W., Kevil, C., Morris, A. J., … Panchatcharam, M. (2018). Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure. Redox Biology, 14, 261–271.
10.1016/j.redox.2017.09.015
CAS PubMed Web of Science® Google Scholar
Chrifi, I., Louzao-Martinez, L., Brandt, M. M., van Dijk, C. G. M., Burgisser, P. E., Zhu, C., … Cheng, C. (2019). CMTM4 regulates angiogenesis by promoting cell surface recycling of VE-cadherin to endothelial adherens junctions. Angiogenesis, 22(1), 75–93.
10.1007/s10456-018-9638-1
CAS PubMed Web of Science® Google Scholar
Coverstone, E. D., Bach, R. G., Chen, L., Bierut, L. J., Li, A. Y., Lenzini, P. A., … Cresci, S. (2018). A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction. Basic Research in Cardiology, 113(5), 38.
10.1007/s00395-018-0697-7
PubMed Web of Science® Google Scholar
Cuadrado, A., Kugler, S., & Lastres-Becker, I. (2018). Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biology, 14, 522–534.
10.1016/j.redox.2017.10.010
CAS PubMed Web of Science® Google Scholar
Darden, J., Payne, L. B., Zhao, H., & Chappell, J. C. (2019). Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation. Angiogenesis, 22(1), 167–183.
10.1007/s10456-018-9648-z
CAS PubMed Web of Science® Google Scholar
Dickinson, J. D., Sweeter, J. M., Warren, K. J., Ahmad, I. M., De Deken, X., Zimmerman, M. C., & Brody, S. L. (2018). Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation. Redox Biology, 14, 272–284.
10.1016/j.redox.2017.09.013
CAS PubMed Web of Science® Google Scholar
Ding, M., Ning, J., Feng, N., Li, Z., Liu, Z., Wang, Y., … Pei, J. (2018). Dynamin-related protein 1-mediated mitochondrial fission contributes to post-traumatic cardiac dysfunction in rats and the protective effect of melatonin. Journal of Pineal Research, 64(1), e12447.
10.1111/jpi.12447
Web of Science® Google Scholar
Erland, L. A. E., Shukla, M. R., Singh, A. S., Murch, S. J., & Saxena, P. K. (2018). Melatonin and serotonin: Mediators in the symphony of plant morphogenesis. Journal of Pineal Research, 64(2), e12452.
10.1111/jpi.12452
Web of Science® Google Scholar
Erland, L. A. E., Yasunaga, A., Li, I. T. S., Murch, S. J., & Saxena, P. K. (2018). Direct visualization of location and uptake of applied melatonin and serotonin in living tissues and their redistribution in plants in response to thermal stress. Journal of Pineal Research, 66(1), e12527.
10.1111/jpi.12527
PubMed Web of Science® Google Scholar
Fan, T., Pi, H., Li, M., Ren, Z., He, Z., Zhu, F., … Zhou, Z. (2018). Inhibiting MT2-TFE3-dependent autophagy enhances melatonin-induced apoptosis in tongue squamous cell carcinoma. Journal of Pineal Research, 64(2), e12457.
10.1111/jpi.12457
Web of Science® Google Scholar
Fernandez Vazquez, G., Reiter, R. J., & Agil, A. (2018). Melatonin increases brown adipose tissue mass and function in Zucker diabetic fatty rats: Implications for obesity control. Journal of Pineal Research, 64(4), e12472.
10.1111/jpi.12472
PubMed Web of Science® Google Scholar
Giatsidis, G., Cheng, L., Haddad, A., Ji, K., Succar, J., Lancerotto, L., … Orgill, D. P. (2018). Noninvasive induction of angiogenesis in tissues by external suction: Sequential optimization for use in reconstructive surgery. Angiogenesis, 21(1), 61–78.
10.1007/s10456-017-9586-1
CAS PubMed Web of Science® Google Scholar
Higgs, C., Crow, Y. J., Adams, D. M., Chang, E., Hayes, D., Jr., Herbig, U., … Clinical Care Consortium for Telomere-associated A (2019). Understanding the evolving phenotype of vascular complications in telomere biology disorders. Angiogenesis, 22(1), 95–102.
10.1007/s10456-018-9640-7
PubMed Web of Science® Google Scholar
Hobson, S. R., Gurusinghe, S., Lim, R., Alers, N. O., Miller, S. L., Kingdom, J. C., & Wallace, E. M. (2018). Melatonin improves endothelial function in vitro and prolongs pregnancy in women with early-onset preeclampsia. Journal of Pineal Research, 65(3), e12508.
10.1111/jpi.12508
PubMed Web of Science® Google Scholar
Ter Horst, E. N., Krijnen, P. A. J., Hakimzadeh, N., Robbers, L., Hirsch, A., Nijveldt, R., … Piek, J. J. (2018). Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats. Basic Research in Cardiology, 114(1), 1.
10.1007/s00395-018-0709-7
PubMed Web of Science® Google Scholar
Jeelani, R., Maitra, D., Chatzicharalampous, C., Najeemuddin, S., Morris, R. T., & Abu-Soud, H. M. (2018). Melatonin prevents hypochlorous acid-mediated cyanocobalamin destruction and cyanogen chloride generation. Journal of Pineal Research, 64(3), e12463.
10.1111/jpi.12463
Web of Science® Google Scholar
Jin, Q., Li, R., Hu, N., Xin, T., Zhu, P., Hu, S., … Zhou, H. (2018). DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biology, 14, 576–587.
10.1016/j.redox.2017.11.004
CAS PubMed Web of Science® Google Scholar
Kiel, A. M., Goodwill, A. G., Baker, H. E., Dick, G. M., & Tune, J. D. (2018). Local metabolic hypothesis is not sufficient to explain coronary autoregulatory behavior. Basic Research in Cardiology, 113(5), 33.
10.1007/s00395-018-0691-0
PubMed Web of Science® Google Scholar
Kim, S. Y., Nair, D. M., Romero, M., Serna, V. A., Koleske, A. J., Woodruff, T. K., & Kurita, T. (2019). Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. Cell Death and Differentiation, 26(3), 502–515.
10.1038/s41418-018-0151-2
CAS PubMed Web of Science® Google Scholar
Li, J., Cai, S. X., He, Q., Zhang, H., Friedberg, D., Wang, F., & Redington, A. N. (2018). Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction. Basic Research in Cardiology, 113(5), 36.
10.1007/s00395-018-0694-x
PubMed Web of Science® Google Scholar
Li, R., Xin, T., Li, D., Wang, C., Zhu, H., & Zhou, H. (2018). Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: The role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biology, 18, 229–243.
10.1016/j.redox.2018.07.011
CAS PubMed Web of Science® Google Scholar
Magni, M., Buscemi, G., Maita, L., Peng, L., Chan, S. Y., Montecucco, A., … Zannini, L. (2019). TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage. Cell Death and Differentiation, 26(5), 918–931.
10.1038/s41418-018-0168-6
CAS PubMed Web of Science® Google Scholar
Man, S., Sanchez Duffhues, G., Ten Dijke, P., & Baker, D. (2019). The therapeutic potential of targeting the endothelial-to-mesenchymal transition. Angiogenesis, 22(1), 3–13.
10.1007/s10456-018-9639-0
CAS PubMed Web of Science® Google Scholar
Mantovani, F., Collavin, L., & Del Sal, G. (2019). Mutant p53 as a guardian of the cancer cell. Cell Death and Differentiation, 26(2), 199–212.
10.1038/s41418-018-0246-9
PubMed Web of Science® Google Scholar
Masaldan, S., Clatworthy, S. A. S., Gamell, C., Meggyesy, P. M., Rigopoulos, A. T., Haupt, S., … Cater, M. A. (2018). Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biology, 14, 100–115.
10.1016/j.redox.2017.08.015
CAS PubMed Web of Science® Google Scholar
Mehra, P., Guo, Y., Nong, Y., Lorkiewicz, P., Nasr, M., Li, Q., … Hill, B. G. (2018). Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair. Basic Research in Cardiology, 113(6), 46.
10.1007/s00395-018-0703-0
PubMed Web of Science® Google Scholar
Merz, J., Albrecht, P., von Garlen, S., Ahmed, I., Dimanski, D., Wolf, D., … Stachon, P. (2018). Purinergic receptor Y2 (P2Y2)- dependent VCAM-1 expression promotes immune cell infiltration in metabolic syndrome. Basic Research in Cardiology, 113(6), 45.
10.1007/s00395-018-0702-1
PubMed Web of Science® Google Scholar
Meyer, I. S., & Leuschner, F. (2018). The role of Wnt signaling in the healing myocardium: A focus on cell specificity. Basic Research in Cardiology, 113(6), 44.
10.1007/s00395-018-0705-y
PubMed Web of Science® Google Scholar
Montoya-Zegarra, J. A., Russo, E., Runge, P., Jadhav, M., Willrodt, A. H., Stoma, S., … Halin, C. (2019). AutoTube: A novel software for the automated morphometric analysis of vascular networks in tissues. Angiogenesis, 22(2), 223–236.
10.1007/s10456-018-9652-3
CAS PubMed Web of Science® Google Scholar
Na, H. J., Yeum, C. E., Kim, H. S., Lee, J., Kim, J. Y., & Cho, Y. S. (2019). TSPYL5-mediated inhibition of p53 promotes human endothelial cell function. Angiogenesis, 22(2), 281–293.
10.1007/s10456-018-9656-z
CAS PubMed Web of Science® Google Scholar
Nwadozi, E., Ng, A., Stromberg, A., Liu, H. Y., Olsson, K., Gustafsson, T., & Haas, T. L. (2019). Leptin is a physiological regulator of skeletal muscle angiogenesis and is locally produced by PDGFRα and PDGFRβ expressing perivascular cells. Angiogenesis, 22(1), 103–115.
10.1007/s10456-018-9641-6
CAS PubMed Web of Science® Google Scholar
Oh, S. E., & Mouradian, M. M. (2018). Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction. Redox Biology, 14, 211–217.
10.1016/j.redox.2017.09.008
CAS PubMed Web of Science® Google Scholar
Paul, S., Gangwar, A., Bhargava, K., & Ahmad, Y. (2018). STAT3-RXR-Nrf2 activates systemic redox and energy homeostasis upon steep decline in pO2 gradient. Redox Biology, 14, 423–438.
10.1016/j.redox.2017.10.013
CAS PubMed Web of Science® Google Scholar
Reddy, K. R. K., Dasari, C., Duscharla, D., Supriya, B., Ram, N. S., Surekha, M. V., … Ummanni, R. (2018). Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is frequently upregulated in prostate cancer, and its overexpression conveys tumor growth and angiogenesis by metabolizing asymmetric dimethylarginine (ADMA). Angiogenesis, 21(1), 79–94.
10.1007/s10456-017-9587-0
CAS PubMed Web of Science® Google Scholar
Renn, T. Y., Huang, Y. K., Feng, S. W., Wang, H. W., Lee, W. F., Lin, C. T., … Chang, H. M. (2018). Prophylactic supplement with melatonin successfully suppresses the pathogenesis of periodontitis through normalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway. Journal of Pineal Research, 64(3), e12464.
10.1111/jpi.12464
Web of Science® Google Scholar
Riehle, C., & Bauersachs, J. (2018). Of mice and men: Models and mechanisms of diabetic cardiomyopathy. Basic Research in Cardiology, 114(1), 2.
10.1007/s00395-018-0711-0
PubMed Web of Science® Google Scholar
Saito, Y., Hikita, H., Nozaki, Y., Kai, Y., Makino, Y., Nakabori, T., … Takehara, T. (2019). DNase II activated by the mitochondrial apoptotic pathway regulates RIP1-dependent non-apoptotic hepatocyte death via the TLR9/IFN-beta signaling pathway. Cell Death and Differentiation, 26(3), 470–486.
10.1038/s41418-018-0131-6
CAS PubMed Web of Science® Google Scholar
Sajib, S., Zahra, F. T., Lionakis, M. S., German, N. A., & Mikelis, C. M. (2018). Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis, 21(1), 1–14.
10.1007/s10456-017-9583-4
CAS PubMed Web of Science® Google Scholar
Serrato, A. J., Romero-Puertas, M. C., Lazaro-Payo, A., & Sahrawy, M. (2018). Regulation by S-nitrosylation of the Calvin-Benson cycle fructose-1,6-bisphosphatase in Pisum sativum. Redox Biology, 14, 409–416.
10.1016/j.redox.2017.10.008
CAS PubMed Web of Science® Google Scholar
Shen, Y. Q., Guerra-Librero, A., Fernandez-Gil, B. I., Florido, J., Garcia-Lopez, S., Martinez-Ruiz, L., … Escames, G. (2018). Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation. Journal of Pineal Research, 64(3), e12461.
10.1111/jpi.12461
Web of Science® Google Scholar
Shi, C., Cai, Y., Li, Y., Li, Y., Hu, N., Ma, S., … Zhou, H. (2018). Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biology, 14, 59–71.
10.1016/j.redox.2017.08.013
CAS PubMed Web of Science® Google Scholar
Sinha, B., Wu, Q., Li, W., Tu, Y., Sirianni, A. C., Chen, Y., … Wang, X. (2018). Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. Journal of Pineal Research, 64(1), e12443.
10.1111/jpi.12443
Web of Science® Google Scholar
Staudacher, V., Trujillo, M., Diederichs, T., Dick, T. P., Radi, R., Morgan, B., & Deponte, M. (2018). Redox-sensitive GFP fusions for monitoring the catalytic mechanism and inactivation of peroxiredoxins in living cells. Redox Biology, 14, 549–556.
10.1016/j.redox.2017.10.017
CAS PubMed Web of Science® Google Scholar
Wei, Y., Chang, Y., Zeng, H., Liu, G., He, C., & Shi, H. (2018). RAV transcription factors are essential for disease resistance against cassava bacterial blight via activation of melatonin biosynthesis genes. Journal of Pineal Research, 64(1), e12454.
10.1111/jpi.12454
Web of Science® Google Scholar
Yao, L., Conforti, F., Hill, C., Bell, J., Drawater, L., Li, J., … Wang, Y. (2019). Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis. Cell Death and Differentiation, 26(5), 943–957.
10.1038/s41418-018-0175-7
CAS PubMed Web of Science® Google Scholar
Zarfati, M., Avivi, I., Brenner, B., Katz, T., & Aharon, A. (2019). Extracellular vesicles of multiple myeloma cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogenesis. Angiogenesis, 22(1), 185–196.
10.1007/s10456-018-9649-y
PubMed Web of Science® Google Scholar
Zhang, H., Jin, B., & Faber, J. E. (2019). Mouse models of Alzheimer's disease cause rarefaction of pial collaterals and increased severity of ischemic stroke. Angiogenesis, 22(2), 263–279.
10.1007/s10456-018-9655-0
CAS PubMed Web of Science® Google Scholar
Zhang, N., Zhang, H., Liu, Y., Su, P., Zhang, J., Wang, X., … Yang, Q. (2019). SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2. Cell Death and Differentiation, 26(5), 843–859.
10.1038/s41418-018-0158-8
CAS PubMed Web of Science® Google Scholar
Zhang, Y., Zhou, H., Wu, W., Shi, C., Hu, S., Yin, T., … Chen, Y. (2016). Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2 + )-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways. Free radical biology & medicine, 95, 278–292.
10.1016/j.freeradbiomed.2016.03.035
CAS PubMed Web of Science® Google Scholar
Zhang, Y., Zou, X., Qian, W., Weng, X., Zhang, L., Zhang, L., … Hou, Z. (2019). Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis. Cell Death and Differentiation, 26(3), 565–579.
10.1038/s41418-018-0147-y
CAS PubMed Web of Science® Google Scholar
Zhao, X. M., Wang, N., Hao, H. S., Li, C. Y., Zhao, Y. H., Yan, C. L., … Zhu, H. B. (2018). Melatonin improves the fertilization capacity and developmental ability of bovine oocytes by regulating cytoplasmic maturation events. Journal of Pineal Research, 64(1), e12445.
10.1111/jpi.12445
Web of Science® Google Scholar
Zhao, Z., Lu, C., Li, T., Wang, W., Ye, W., Zeng, R., … Liu, C. (2018). The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial. Journal of Pineal Research, 65(4), e12521.
10.1111/jpi.12521
PubMed Web of Science® Google Scholar
Zhou, H., Du, W., Li, Y., Shi, C., Hu, N., Ma, S., … Ren, J. (2018). Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. Journal of Pineal Research, 64(1), e12450.
10.1111/jpi.12450
Web of Science® Google Scholar
Zhou, H., Li, N., Yuan, Y., Jin, Y. G., Guo, H., Deng, W., & Tang, Q. Z. (2018). Activating transcription factor 3 in cardiovascular diseases: A potential therapeutic target. Basic Research in Cardiology, 113(5), 37.
10.1007/s00395-018-0698-6
PubMed Web of Science® Google Scholar
Zhou, H., Shi, C., Hu, S., Zhu, H., Ren, J., & Chen, Y. (2018). BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis, 21(3), 599–615.
10.1007/s10456-018-9611-z
CAS PubMed Web of Science® Google Scholar
Zhou, H., Wang, J., Zhu, P., Zhu, H., Toan, S., Hu, S., … Chen, Y. (2018). NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Research in Cardiology, 113(4), 23.
10.1007/s00395-018-0682-1
PubMed Web of Science® Google Scholar
Zhou, H., Zhu, P., Wang, J., Zhu, H., Ren, J., & Chen, Y. (2018). Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death and Differentiation, 25(6), 1080–1093.
10.1038/s41418-018-0086-7
CAS PubMed Web of Science® Google Scholar
Zhou, Y. Q., Liu, D. Q., Chen, S. P., Sun, J., Zhou, X. R., Rittner, H., … Ye, D. W. (2018). Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain. Redox Biology, 14, 391–397.
10.1016/j.redox.2017.10.011
CAS PubMed Web of Science® Google Scholar
Zhu, H., Jin, Q., Li, Y., Ma, Q., Wang, J., Li, D., … Chen, Y. (2018). Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca(2 + )]c/VDAC-[Ca(2 + )]m axis by activation of MAPK/ERK signaling pathway. Cell Stress and Chaperones, 23(1), 101–113.
10.1007/s12192-017-0827-4
CAS PubMed Web of Science® Google Scholar
Zhu, P., Hu, S., Jin, Q., Li, D., Tian, F., Toan, S., … Chen, Y. (2018). Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biology, 16, 157–168.
10.1016/j.redox.2018.02.019
CAS PubMed Web of Science® Google Scholar
Zhu, Y., Wang, P., Zhang, L., Bai, G., Yang, C., Wang, Y., … Zou, D. (2019). Superhero rictor promotes cellular differentiation of mouse embryonic stem cells. Cell Death and Differentiation, 26(5), 958–968.
10.1038/s41418-018-0177-5
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume235, Issue2

February 2020

Pages 1504-1514

Proinflammation effect of Mst1 promotes BV-2 cell death via augmenting Drp1-mediated mitochondrial fragmentation and activating the JNK pathway

Abstract

1 INTRODUCTION