Acute mental stress induces mitochondrial bioenergetic crisis and hyper-fission along with aberrant mitophagy in the gut mucosa in rodent model of stress-related mucosal disease

De, Rudranil; Mazumder, Somnath; Sarkar, Souvik; Debsharma, Subhashis; Siddiqui, Akhlaq A.; Saha, Shubhra Jyoti; Banerjee, Chinmoy; Nag, Shiladitya; Saha, Debanjan; Bandyopadhyay, Uday

doi:10.1016/j.freeradbiomed.2017.10.009

Cited by 40 publications

(30 citation statements)

References 73 publications

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“…Interestingly, enhanced fission was found to be positively associated with a significant compromise in mitochondrial health and functionality, as evident from membrane depolarization and ATP formation, leading to cellular bioenergetic crisis. Functionally compromised mitochondria are normally eliminated from the cell (31,32), leading to a partial reduction in mitochondrial mass (33). siMIF-induced reduction in the mtDNA copy number is therefore a prominent proof of enhanced clearance of the functionally compromised mitochondria, further justifying the radical depletion in ATP upon MIF silencing.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, 2 g of RNA was used for cDNA preparation using a RevertAid First Strand cDNA synthesis kit (Thermo Fisher Scientific). The obtained cDNA were diluted and used for qPCR reaction as mentioned previously (33) with primers against NF-B and GAPDH. The primer sequences were as follows: NF-B, forward, 5Ј-CCAGACCAACAACAA-CCCCT-3Ј, and reverse, 5Ј-TCACTCGGCAGATCTTGAGC-3Ј; and GAPDH, forward, 5Ј-AGTATGACTCTACCCAC-GGC-3Ј, and reverse, 5Ј-TGAAGACGCCAGTAGACTCC-3Ј.…”

Section: Rna Isolation and Real-time Rt-pcrmentioning

confidence: 99%

“…The mitochondrial content was assessed by calculating the ratio of mtDNA and nuclear DNA, as mentioned previously (33), with minor modifications. Briefly, control siRNA and siMIF-treated cells were subjected to DNA isolation using a DNA isolation kit (Qiagen).…”

Section: Analysis Of Mitochondrial Copy Numbermentioning

confidence: 99%

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Macrophage migration inhibitory factor regulates mitochondrial dynamics and cell growth of human cancer cell lines through CD74–NF-κB signaling

De¹,

Sarkar²,

Mazumder

et al. 2018

Journal of Biological Chemistry

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The indispensable role of macrophage migration inhibitory factor (MIF) in cancer cell proliferation is unambiguous, although which specific roles the cytokine plays to block apoptosis by preserving cell growth is still obscure. Using different cancer cell lines (AGS, HepG2, HCT116, and HeLa), here we report that the silencing of MIF severely deregulated mitochondrial structural dynamics by shifting the balance toward excess fission, besides inducing apoptosis with increasing sub-G 0 cells. Furthermore, enhanced mitochondrial Bax translocation along with cytochrome c release, down-regulation of Bcl-xL, and Bcl-2 as well as up-regulation of Bad, Bax, and p53 indicated the activation of a mitochondrial pathway of apoptosis upon MIF silencing. The data also indicate a concerted down-regulation of Opa1 and Mfn1 along with a significant elevation of Drp1, cumulatively causing mitochondrial fragmentation upon MIF silencing. Upregulation of Drp1 was found to be further coupled with fissogenic serine 616 phosphorylation and serine 637 dephosphorylation, thus ensuring enhanced mitochondrial translocation. Interestingly, MIF silencing was found to be associated with decreased NF-B activation. In fact, NF-B knockdown in turn increased mitochondrial fission and cell death. In addition, the silencing of CD74, the cognate receptor of MIF, remarkably increased mitochondrial fragmentation in addition to preventing cell proliferation, inducing mitochondrial depolarization, and increasing apoptotic cell death. This indicates the active operation of a MIF-regulated CD74 -NF-B signaling axis for maintaining mitochondrial stability and cell growth. Thus, we propose that MIF, through CD74, constitutively activates NF-B to control mitochondrial dynamics and stability for promoting carcinogenesis via averting apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Rna Isolation and Real-time Rt-pcrmentioning

confidence: 99%

See 1 more Smart Citation

Macrophage migration inhibitory factor regulates mitochondrial dynamics and cell growth of human cancer cell lines through CD74–NF-κB signaling

De¹,

Sarkar²,

Mazumder

et al. 2018

Journal of Biological Chemistry

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“…In the hippocampus, chronic stress altered the phosphorylation of mitochondrial GRs, whereas in the prefrontal cortex, chronic stress significantly increased mitochondrial GR levels ( Adzic et al, 2013 ). In the gut, stress increased serum CORT levels, which activated GR recruitment to instigate decreased ETC complex I activity, hyper-fission, and accumulation of ROS inducing apoptosis ( De et al, 2017 ). This is the intrinsic pathway of apoptosis, which is affected by oxidative stress, elevated Ca2+ levels, and damaged DNA ( Green and Kroemer, 1998 ; Kroemer et al, 2007 ).…”

Section: Apoptosismentioning

confidence: 99%

Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression

et al. 2018

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Human and animal studies suggest an intriguing link between mitochondrial diseases and depression. Although depression has historically been linked to alterations in monoaminergic pharmacology and adult hippocampal neurogenesis, new data increasingly implicate broader forms of dampened plasticity, including plasticity within the cell. Mitochondria are the cellular powerhouse of eukaryotic cells, and they also regulate brain function through oxidative stress and apoptosis. In this paper, we make the case that mitochondrial dysfunction could play an important role in the pathophysiology of depression. Alterations in mitochondrial functions such as oxidative phosphorylation (OXPHOS) and membrane polarity, which increase oxidative stress and apoptosis, may precede the development of depressive symptoms. However, the data in relation to antidepressant drug effects are contradictory: some studies reveal they have no effect on mitochondrial function or even potentiate dysfunction, whereas other studies show more beneficial effects. Overall, the data suggest an intriguing link between mitochondrial function and depression that warrants further investigation. Mitochondria could be targeted in the development of novel antidepressant drugs, and specific forms of mitochondrial dysfunction could be identified as biomarkers to personalize treatment and aid in early diagnosis by differentiating between disorders with overlapping symptoms.

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“… 15 , 16 Intriguingly, stress has been reported to impact the mitochondria function and dynamics, which raised the possibility that stress-inhibited IFN-β response might stem from the deterioration of MAVS antivirus signaling. 17 , 18 In this study, we utilized restraint stress mouse model to elucidate the potential mechanism responsible for stress-increased susceptibility to influenza. Our results demonstrated that the increase of corticosterone (CORT), as a result of stress response, hindered IFN-β expression to enhance virus susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-β responses by Mfn2-mediated ubiquitin degradation of MAVS

Luo

Liu

Jiang

et al. 2020

Sig Transduct Target Ther

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Although stress has been known to increase the susceptibility of pathogen infection, the underlying mechanism remains elusive. In this study, we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus (H1N1) and obviously aggravated lung inflammation. Corticosterone (CORT), a main type of glucocorticoids in rodents, was secreted in the plasma of stressed mice. We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling (MAVS) protein-transduced IFN-β production without affecting its mRNA level, while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice. Mechanistically, the effect of CORT was mediated by proteasome-dependent degradation of MAVS, thereby resulting in the impediment of MAVS-transduced IFN-β generation in vivo and in vitro. Furthermore, RNA-seq assay results indicated the involvement of Mitofusin 2 (Mfn2) in this process. Gain- and loss-of-function experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS. Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2 (HR1), MAVS (C-terminal/TM) and SYVN1 (TM). Collectively, our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a ‘fine tuning’ of antiviral innate immunity in response to influenza infection under stress.

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Acute mental stress induces mitochondrial bioenergetic crisis and hyper-fission along with aberrant mitophagy in the gut mucosa in rodent model of stress-related mucosal disease

Cited by 40 publications

References 73 publications

Macrophage migration inhibitory factor regulates mitochondrial dynamics and cell growth of human cancer cell lines through CD74–NF-κB signaling

Macrophage migration inhibitory factor regulates mitochondrial dynamics and cell growth of human cancer cell lines through CD74–NF-κB signaling

Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression

Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-β responses by Mfn2-mediated ubiquitin degradation of MAVS

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