The phosphorylation of Metaxin 1 controls Bak activation during TNFα induced cell death

Petit, Elise; Cartron, Pierre-François; Oliver, Lisa; Vallette, François M.

doi:10.1016/j.cellsig.2016.11.008

Cited by 15 publications

(21 citation statements)

References 35 publications

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“…Further experiments aiming to restore MTX1 levels in patients’ cells by inhibiting its degradation should validate this point, with potentially important therapeutic consequences. Indeed, based on previous results, MTX1 loss, even more than MTX2 loss, could be a major determinant of apoptosis resistance in patients’ cells 36 , with downstream “domino” noxious effects. Furthermore, since VDAC2, the third major component of the SAM complex, was not lost upon MTX2 deficiency 31 , its presence may be able to rescue MTX1 localization at the OMM upon inhibition of its degradation.…”

Section: Discussionmentioning

confidence: 92%

“…Given the involvement of MTX2 and MTX1 in apoptosis response to TNFα 33 – 36 , we next investigated whether MTX2 and MTX1 loss could lead to apoptosis resistance in patients’ primary fibroblasts. The number of dead cells upon apoptosis triggering with either staurosporine or TNFα/cycloheximide (CHX) was significantly reduced in patient compared to control fibroblasts (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These interactions form large “mitochondrial intermembrane space bridging” complexes that help shaping and stabilizing CJs 31 , 32 . In addition, several studies identified a role for MTX1 and MTX2 in TNF-α-induced apoptosis, through the interaction with the pro-apoptotic protein Bak 33 – 36 . The functional studies we report in MADaM patient-derived primary fibroblasts show that the loss of MTX2 and MTX1 causes mitochondrial network fragmentation, decreased oxidative phosphorylation, resistance to apoptosis triggering by TNF-α, increased senescence and autophagy, and reduced proliferation; furthermore, it secondarily impacts nuclear morphology in a fashion that resembles HGPS and other progeroid laminopathies, probably underlying common clinical features.…”

Section: Introductionmentioning

confidence: 99%

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Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

et al. 2020

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Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

et al. 2020

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“…33 Bax could trigger the release of cytochrome c into the cytosol via regulation of the mitochondrial permeability. 34 After that, cytochrome c recruits caspase-9 to form the apoptosome, and then induces caspase-3 activation and induces apoptosis. 35 In this study, downregulation of hsa_circ_0059955 decreased the MMP in NP cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Knockdown of hsa_circ_0059955 Induces Apoptosis and Cell Cycle Arrest in Nucleus Pulposus Cells via Inhibiting <em>Itchy E3 Ubiquitin Protein Ligase</em></p>

Kong¹,

Gu²,

Zhang³

et al. 2020

DDDT

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Background: Circular RNAs (circRNAs) play an important role in the progression of intervertebral disc (IVD) degeneration (IVDD). Using bioinformatics analysis, we have found that the expression of circRNA hsa_circ_0059955 was significantly downregulated in IVDD tissues. However, the relevant mechanism of hsa_circ_0059955 in the progression of IVDD remains unclear. Methods: CCK-8 and flow cytometry assays were used to evaluate cell proliferation and apoptosis. In addition, Western blot assay was used to detect the expressions of ITCH, p73, CDK2 in nucleus pulposus (NP) cells. Moreover, a puncture-induced IVDD rat model was established to explore the role of hsa_circ_0059955 in IVDD. Results: The level of hsa_circ_0059955 was significantly decreased in IVDD tissues from IVDD patients. Itchy E3 ubiquitin protein ligase (ITCH) is the host gene of hsa_circ_0059955, and downregulation of hsa_circ_0059955 significantly decreased the expression of ITCH in NP cells. In addition, downregulation of hsa_circ_0059955 markedly inhibited proliferation and induced apoptosis and cell cycle arrest in NP cells. Moreover, in vivo study illustrated that overexpression of hsa_circ_0059955 ameliorated IVDD in rats. Conclusion: Downregulation of hsa_circ_0059955 could induce apoptosis and cell cycle arrest in NP cells in vitro, while overexpression of hsa_circ_0059955 attenuated the IVDD in a puncture-induced rat model in vivo. Therefore, hsa_circ_0059955 might serve as a therapeutic target for the treatment of IVDD.

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“…The Bcl-2 family of proteins comprises three main groups classified according to Bcl-2 homology (BH) regions and function: (1) the multidomain antiapoptotic group (Bcl-2, Bcl-xl, and MCL-1); (2) the multidomain proapoptotic group (Bax and Bak); and (3) the BH3-only proapoptotic group (Bid, Bim, Bad, and Puma). Bak and Bax play pivotal roles in the regulation of mitochondrial permeability to trigger the release of mitochondrial proapoptotic factors, such as cytochrome C and Smac [6]. Additionally, mutations in the Bak gene have been indicated in human gastrointestinal cancers, and reduction in Bak protein levels has been observed in human gastric and colorectal tumors, indicating the critical role of Bak in pathogenesis of various tumors [7].…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Knockout of Bak Mediates Bax Translocation to Mitochondria in response to TNFα/CHX-induced Apoptosis

Zhang

Niu

Zhao

et al. 2019

BioMed Research International

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TNFα/CHX-induced apoptosis is dependent on caspase-8 activation and regulated by Bcl-2. However, the specific participants and precise mechanisms underlying this apoptotic pathway are poorly understood. The proapoptotic proteins Bak and Bax—members of the Bcl-2 family—are essential for the functioning of the mitochondrial apoptotic pathway. In this study, we used the CRISPR/Cas9 system to knockout Bak in the human SH-SY5Y cell line and determined the effects of this knockout on TNFα/CHX-induced apoptosis. Our data showed that overexpression of Bcl-2 dramatically prevented TNFα/CHX-induced apoptosis, and then pro-apoptotic protein Bak was downregulated and became more resistant to TNFα/CHX-induced apoptosis, because both TNFα/CHX-induced PARP cleavage and caspase activation were blocked in BAK−/− cells or using specific siRNA, whereas Bax was dispensable in TNFα/CHX-induced apoptosis, as evidenced using specific siRNA. Bax translocated from the cytosol into the mitochondria in response to TNFα/CHX, and CRISPR/Cas9 knockout of Bak significantly decreased this translocation. These results indicate that TNFα/CHX-induced apoptosis does not occur in Bak−/− cells, suggesting that TNFα/CHX-induced apoptosis is Bak-dependent but Bax-independent.

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The phosphorylation of Metaxin 1 controls Bak activation during TNFα induced cell death

Cited by 15 publications

References 35 publications

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

<p>Knockdown of hsa_circ_0059955 Induces Apoptosis and Cell Cycle Arrest in Nucleus Pulposus Cells via Inhibiting <em>Itchy E3 Ubiquitin Protein Ligase</em></p>

CRISPR/Cas9 Knockout of Bak Mediates Bax Translocation to Mitochondria in response to TNFα/CHX-induced Apoptosis

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