Metaxins 1 and 2, two proteins of the mitochondrial protein sorting and assembly machinery, are essential for Bak activation during TNF alpha triggered apoptosis

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

doi:10.1016/j.cellsig.2014.04.021

Cited by 29 publications

(33 citation statements)

References 37 publications

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“…We have recently identified Mtx2 and 1 as receptors for Bak during TNFα/CHX induced apoptosis (6). Quite interestingly, recent results have shown that TOM machinery is essential in the mitochondrial elimination during autophagy by controlling the PINK-PARK pathway (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…in an acellular assay to study the association of an in vitro translated Bak (IVT-Bak) (Cartron et al, 2014). As illustrated in Figure 1C, Bak was not associated to MTX2-deficient HMF and a mild trypsin treatment designed to proteolyze exposed domains of Bak (6) …”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…Mtx1 has been shown to be required for the TNF-induced cell death (15) and that its deficiency led to mitochondrial anti-apoptotic phenotypes (16). Recently, we have shown that Bak interacted with Mtx2 in resting cells and with Mtx1 upon TNF treatment (6) The role and the regulation of apoptosis by the different mitochondrial receptors of the Bcl-2 family are not completely understood and it has been speculated that it could affect cell death only under specific physiological situations (17,18). In this study, we show that the…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that Metaxin 1 and 2 interacted sequentially with Bak upon induction of apoptosis by a TNF/ cycloheximide (TNF/CHX) treatment (6). We studied the effect of the knock down of the expression of Mtx1 and Mtx2 by interference RNA (shRNA) as previously described (6) on the subcellular localization of Bak in resting and TNF/ CHX treated primary cultures from Bax deficient Glioblastoma multiforme patients (BdGM) (6).…”

Section: Role Of Mtx1 and Mtx2 In Bak Association With Mitochondriamentioning

confidence: 99%

“…We studied the effect of the knock down of the expression of Mtx1 and Mtx2 by interference RNA (shRNA) as previously described (6) on the subcellular localization of Bak in resting and TNF/ CHX treated primary cultures from Bax deficient Glioblastoma multiforme patients (BdGM) (6). We used as a control two sh Scrambled and sh TOM22, directed against another protein import receptor which has been involved in Bax docking to mitochondria (21) and the analysis of Bcl-2 subcellular localization as it is a protein closely related to Bak (3).…”

Section: Role Of Mtx1 and Mtx2 In Bak Association With Mitochondriamentioning

confidence: 99%

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

Petit

Cartron

Oliver

et al. 2017

Cellular Signalling

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International audienceThe proapoptotic protein Bak is implicated in the execution phase of apoptosis, a cell death program. Bak is essentially mitochondrial and during early steps of apoptosis undergoes conformational changes that lead to its full membrane integration in mitochondria and the subsequent liberation of pro-apoptotic mitochondrial proteins. Little is known about the partners and mechanisms implicated in the activation of Bak. We have recently shown that Bak is incorporated into a Voltage dependent anionic channel of type 2 (VDAC2)/Metaxin 1(Mtx1)/Metaxin 2 (Mtx2) multi-protein complex in both resting and dying cells. Here, we show that, after the induction of apoptosis, Bak switches from its association with Mtx2 and VDAC2 to a closer association with Mtx1. This change of partners is under the control of a tyrosine phosphorylation of Mtx1 by c-Abl

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Section: Discussionmentioning

confidence: 99%

Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Role Of Mtx1 and Mtx2 In Bak Association With Mitochondriamentioning

confidence: 99%

Section: Role Of Mtx1 and Mtx2 In Bak Association With Mitochondriamentioning

confidence: 99%

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

Petit

Cartron

Oliver

et al. 2017

Cellular Signalling

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Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

Zinngrebe

Schlichtig

Kraus

et al. 2019

Intl Journal of Cancer

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Second mitochondria‐derived activator of caspase (SMAC) mimetics (SMs) targeting inhibitor of apoptosis proteins (IAPs) activate cell death pathways, and are currently being evaluated in clinical trials. Their successful therapeutic implementation requires upfront identification of patients who could benefit from a SM‐based treatment but biomarkers for SM sensitivity have not yet been described. Here, we analyzed the intrinsic activity of two monovalent (AT406 and LCL161) and two bivalent (Birinapant and BV6) SMs on unselected patient‐derived pediatric precursor B‐cell acute lymphoblastic leukemia (BCP‐ALL) identifying a subset of patient samples to be particularly sensitive to SM‐induced cell death. This subset was defined by a characteristic gene expression signature with 127 differentially regulated genes, amongst them TNFRSF1A encoding TNFR1, and a critical role of TNFR1 in SM‐induced cell death in sensitive BCP‐ALL was confirmed on the functional level. Interestingly, samples with intermediate or low sensitivity to SMs were sensitized to SM‐induced cell death by inhibition of caspases using zVAD.fmk or Emricasan, a pan‐caspase inhibitor in clinical trials. When we compared our expression data to published data sets, we identified an overlap of four genes to be commonly differentially regulated in SM‐sensitive BCP‐ALL, that is, TSPAN7, DIPK1C, MTX2 and, again, TNFRSF1A. Functional testing revealed that this set of genes identified samples with high sensitivity to SM treatment. In summary, our data suggest using this gene signature as biomarker predicting response to SM treatment and point to the development of new combinatorial treatments consisting of SMs and pan‐caspase inhibitors for a successful clinical implementation of SMs in treatment of BCP‐ALL.

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Mitochondria as Signaling Platforms

Yoboue

Manon

Camougrand

2019

Mitochondria in Obesity and Type 2 Diabetes

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Metaxins 1 and 2, two proteins of the mitochondrial protein sorting and assembly machinery, are essential for Bak activation during TNF alpha triggered apoptosis

Cited by 29 publications

References 37 publications

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

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

Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

Mitochondria as Signaling Platforms

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