Mitochondria-Associated Membranes (MAMs) are involved in Bax mitochondrial localization and cytochrome c release

Légiot, Alexandre; Céré, Claire; Dupoiron, Thibaud; Kaabouni, Mohamed; Manon, Stéphen

doi:10.1101/443606

Cited by 5 publications

(7 citation statements)

References 43 publications

(52 reference statements)

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“…The likely interaction between BI1 and PHB2 noted in our current study is somewhat different from the inter-organelle communication between ER and mitochondria 58. Several mitochondrial pathophysiological processes are temporally and spatially linked to ER, such as fission 59, calcium recycling 60, ROS production61, and apoptosis62. However, findings revealed in our current study did not favor direct interaction between ER and mitochondria for BI1-PHB2 interaction.…”

Section: Discussioncontrasting

confidence: 89%

Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2

Wang¹,

Zhu²,

Li³

et al. 2020

Theranostics

116

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Bax inhibitor-1 (BI1) conveys anti-apoptotic signals for mitochondria while prohibitin 2 (PHB2) is implicated in sustaining mitochondrial morphology and function. However, their regulatory roles in acute kidney injury (AKI) are largely unknown.Methods: In human patients with AKI, levels of BI1 in urine and plasma were determined using ELISA. An experimental model of AKI was established using ATP depletion-mediated metabolic stress and ischemia-reperfusion injury (IRI) in primary tubule cells and BI1 transgenic mice, respectively. Western blots, ELISA, qPCR, immunofluorescence, RNA silencing, and domain deletion assay were employed to evaluate the roles of BI1 and PHB2 in the preservation of mitochondrial integrity.Results: Levels of BI1 in urine and plasma were decreased in patients with AKI and its expression correlated inversely with renal function. However, reconstitution of BI1 in a murine AKI model was capable of alleviating renal failure, inflammation and tubular death. Further molecular scrutiny revealed that BI1 preserved mitochondrial genetic integrity, reduced mitochondrial oxidative stress, promoted mitochondrial respiration, inhibited excessive mitochondrial fission, improved mitophagy and suppressed mitochondrial apoptosis. Intriguingly, levels of the mitochondria-localized PHB2 were sustained by BI1 and knockdown of PHB2 abolished the mitochondrial- and renal- protective properties of BI1. Furthermore, BI1 promoted PHB2 retention within mitochondria through direct interaction with cytoplasmic PHB2 to facilitate its mitochondrial import. This was confirmed by the observation that the C-terminus of BI1 and the PHB domain of PHB2 were required for the BI1-PHB2 cross-linking.Conclusion: Our data have unveiled an essential role of BI1 as a master regulator of renal tubule function through sustaining mitochondrial localization of PHB2, revealing novel therapeutic promises against AKI.

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Section: Discussioncontrasting

confidence: 89%

Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2

Wang¹,

Zhu²,

Li³

et al. 2020

Theranostics

116

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“…Transformed cells were selected on the basis of geneticin resistance and verified by a polymerase chain reaction. The destabilization of ERMES in the W303/Δmdm34 was reported previously 16 .…”

Section: Yeast Experimentssupporting

confidence: 74%

“…MAM are crucial membranes juxtaposed to the mitochondria, mostly constituted by ER-mitochondria apposition, whose role in apoptosis is raising since their regulation of Bax and Bak activity was demonstrated 35 . In the early apoptosis, biological material is exchanged between ER and mitochondria, among which ceramides 6 and proteins, including Bax 16 and Bcl2 as described in this study. The regulation of MAM dynamics, defining the proximity between organelles and probably the ability of molecules to transfer from one organelle to the other, thereby appears as a new player in the regulation of MOMP.…”

Section: Discussionmentioning

confidence: 98%

“…In yeast, a single protein complex, namely ERMES, is responsible for MAM stability, making it a good model to investigate the role of MAM in the mechanism. As MDM34 deletion impairs Bax mitochondrial localization and apoptotic activity 16 , it also disturbs Bcl2 localization. In resting conditions, MAM destabilization increases mitochondrial Bcl2 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Figure 4D shows that Bcl2 mitochondrial localization (gray bars) is increased when apoptosis is induced. We then deleted mdm34, a gene coding for a protein of the ERMES complex, implicated in MAM stabilization 16 . MDM34 deletion raised the mitochondrial localization of Bcl2, suggesting that Bcl2 is actively pulled out of the MOM through the MAM in resting yeast cells.…”

Section: Bcl2 Interacts With Tom20 In Yeastmentioning

confidence: 99%

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TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis

et al. 2021

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In this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2–TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER–mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2–TOM20 interaction is thus an additional player in the control of apoptosis.

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Ceramide Domains in Health and Disease: A Biophysical Perspective

Ventura

Mestre

Silva

2019

Advances in Experimental Medicine and Biology

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Mitochondria-Associated Membranes (MAMs) are involved in Bax mitochondrial localization and cytochrome c release

Cited by 5 publications

References 43 publications

Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2

Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2

TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis

Ceramide Domains in Health and Disease: A Biophysical Perspective

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