IκΒα inhibits apoptosis at the outer mitochondrial membrane independently of <scp>NF</scp>‐κB retention

Pazarentzos, Evangelos; Mahul‐Mellier, Anne‐Laure; Datler, Christoph; Chaisaklert, Wanwisa; Hwang, Ming-Shih; Kroon, Jan; Ding, Qize; Osborne, Foy N; Al-Rubaish, Abdullah M.; Al-Ali, Amein K.; Mazarakis, Nicholas D.; Aboagye, Eric O.; Grimm, Stefan

doi:10.15252/embj.201488183

Cited by 33 publications

(36 citation statements)

References 51 publications

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“…Finally, the localization of NF-κB and IκBα in the mitochondrion and their regulation of mitochondrial DNA activities should be investigated. NF-κB p65 and IκBα have been detected in the mitochondrial (Bottero et al, 2001;Zamora et al, 2004;Pazarentzos et al, 2014). In addition, TNF-α stimulation induces mitochondrial IκBα phosphorylation and proteasome-independent IκBα degradation and promotes the accumulation of mitochondrial NF-κB p65, thus leading to decreased expression of mitochondrial DNA cytochrome c oxidase III and cytochrome b in U937 cells (Cogswell et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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The nuclear factor-kappa B (NF-κB) signaling pathway regulates a variety of biological functions in the body, and its abnormal activation contributes to the pathogenesis of many diseases, such as cardiovascular and respiratory diseases and cancers. Therefore, to ensure physiological homeostasis of body systems, this pathway is strictly regulated by IκBα transcription, IκBα synthesis, and the IκBα-dependent nuclear transport of NF-κB. Particularly, the post-translational modifications of IκBα including phosphorylation, ubiquitination, SUMOylation, glutathionylation and hydroxylation are crucial in the abovementioned regulatory process. Because of the importance of the NF-κB pathway in maintaining body homeostasis, understanding the post-translational modifications of IκBα can not only provide deeper insights into the regulation of NF-κB pathway but also contribute to the development of new drug targets and biomarkers for the diseases.

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Section: Discussionmentioning

confidence: 99%

Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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“…In the absence of any stimulus, RelA is sequestered in the cytosol by a protein, inhibitor of B (IB). Interestingly, a recent study demonstrated that IB also localizes to the mitochondria, where it associates with VDAC1 and stabilizes the closed state of the PTP (38). It would be interesting to investigate whether miR-7, by down-regulating RelA, makes more IB available to the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression

Chaudhuri

Choi

Kabaria

et al. 2016

Journal of Biological Chemistry

106

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Mitochondrial dysfunction is one of the major contributors to neurodegenerative disorders including Parkinson disease. The mitochondrial permeability transition pore is a protein complex located on the mitochondrial membrane. Under cellular stress, the pore opens, increasing the release of proapoptotic proteins, and ultimately resulting in cell death. MicroRNA-7 (miR-7) is a small non-coding RNA that has been found to exhibit a protective role in the cellular models of Parkinson disease. In the present study, miR-7 was predicted to regulate the function of mitochondria, according to gene ontology analysis of proteins that are down-regulated by miR-7. Indeed, miR-7 overexpression inhibited mitochondrial fragmentation, mitochondrial depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to 1-methyl-4-phenylpyridinium (MPP ؉ ) in human neuroblastoma SH-SY5Y cells. In addition, several of these findings were confirmed in mouse primary neurons. Among the mitochondrial proteins identified by gene ontology analysis, the expression of voltage-dependent anion channel 1 (VDAC1), a constituent of the mitochondrial permeability transition pore, was down-regulated by miR-7 through targeting 3-untranslated region of VDAC1 mRNA. Similar to miR-7 overexpression, knockdown of VDAC1 also led to a decrease in intracellular reactive oxygen species generation and subsequent cellular protection against MPP ؉ . Notably, overexpression of VDAC1 without the 3-UTR significantly abolished the protective effects of miR-7 against MPP ؉ -induced cytotoxicity and mitochondrial dysfunction, suggesting that the protective effect of miR-7 is partly exerted through promoting mitochondrial function by targeting VDAC1 expression. These findings point to a novel mechanism by which miR-7 accomplishes neuroprotection by improving mitochondrial health.The mitochondrial permeability transition pore (PTP), 2 which spans both the outer and the inner mitochondrial membranes, is a conductance channel responsible for maintaining the mitochondrial membrane potential. The mitochondrial PTP consists of three proteins: voltage-dependent anion channel 1 (VDAC1), adenine nucleotide transporter (ANT), and cyclophilin D (1). VDAC1 and ANT are integral membrane proteins of the outer and inner mitochondrial membranes, respectively. Together, these two proteins form the conductance channel of the mitochondrial PTP. Cyclophilin D is a mitochondrial matrix protein that associates with ANT and modulates pore function. Under normal physiological conditions, the mitochondrial PTP is maintained in a closed state, allowing mitochondria to remain polarized. Stressful stimuli, such as oxidative stress and accumulation of unfolded proteins, lead to the opening of the mitochondrial PTP (1). As a result, the mitochondrial membrane potential is dissipated, causing depolarization of mitochondria, decrease in ATP production, swelling of mitochondria, efflux of mitochondrial calcium, generation of reactive oxygen spec...

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“…In a recent study by Pazarentzos et al (2014), IκBα was found to exert pro-apoptotic activity as it inhibited the anti-apoptotic NF-κB. In most cells, the activation of NF-κB leads to downstream target gene expression that triggers cell death resistance (Luo et al, 2005).…”

Section: Nf-κb and Apoptosis In The Mitochondriamentioning

confidence: 99%

“…In this study, it was shown that a novel apoptosis function was due to IκBα, the subunit that inhibits NF-κB’s activation. Pazarentzos et al (2014) found that IκBα localizes to the OMM where it interacts with a voltage dependent anion channel (VDAC) and mitochondrial hexokinase II (HKII) to stabilize this complex and prevent Bax-mediated cytochrome c release for apoptosis. Bax is a member of the Bcl-2 family of proteins, which have been shown to be regulators of programed cell death (Karbowski et al, 2006).…”

Section: Nf-κb and Apoptosis In The Mitochondriamentioning

confidence: 99%

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

Albensi

2019

Front. Cell Dev. Biol.

261

198

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A large body of literature supports the idea that nuclear factor kappa B (NF-κB) signaling contributes to not only immunity, but also inflammation, cancer, and nervous system function. However, studies on NF-κB activity in mitochondrial function are much more limited and scattered throughout the literature. For example, in 2001 it was first published that NF-κB subunits were found in the mitochondria, including not only IkBα and NF-κB p65 subunits, but also NF-κB pathway proteins such as IKKα, IKKβ, and IKKγ, but not much follow-up work has been done to date. Upon further thought the lack of studies on NF-κB activity in mitochondrial function is surprising given the importance and the evolutionary history of both NF-κB and the mitochondrion. Both are ancient in their appearance in our biological record where both contribute substantially to cell survival, cell death, and the regulation of function and/or disease. Studies also show NF-κB can influence mitochondrial function from outside the mitochondria. Therefore, it is essential to understand the complexity of these roles both inside and out of this organelle. In this review, an attempt is made to understand how NF-κB activity contributes to overall mitochondrial function – both inside and out. The discussion at times is speculative and perhaps even provocative to some, since NF-κB does not yet have defined mitochondrial targeting sequences for some nuclear-encoded mitochondrial genes and mechanisms of mitochondrial import for NF-κB are not yet entirely understood. Also, the data associated with the mitochondrial localization of proteins must be yet further proved with additional experiments.

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IκΒα inhibits apoptosis at the outer mitochondrial membrane independently of NF‐κB retention

Cited by 33 publications

References 51 publications

Post-translational Modifications of IκBα: The State of the Art

Post-translational Modifications of IκBα: The State of the Art

MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

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