Membrane Remodeling Induced by the Dynamin-Related Protein Drp1 Stimulates Bax Oligomerization

Montessuit, Sylvie; Somasekharan, Syam Prakash; Terrones, Oihana; Lucken-Ardjomande, Safa; Herzig, Sébastien; Schwarzenbacher, Robert; Manstein, Dietmar J.; Bossy‐Wetzel, Ella; Basáñez, Gorka; Meda, Paolo; Martinou, Jean‐Claude

doi:10.1016/j.cell.2010.08.017

Cited by 372 publications

(369 citation statements)

References 54 publications

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“…42 These events can be simulated in vitro using synthetic membranes, and in this system, it has been shown that the presence of CL in the membrane was required for tBID recruitment and BAX insertion. 13,[15][16][17][18][19] These results raised the possibility that CL could have a similar role in mitochondria during apoptosis. However, involvement of CL in BAX activation has been questioned, in particular, in yeast.…”

Section: Discussionmentioning

confidence: 95%

“…11 It has also been proposed to have an important role in the regulation of MOMP, 12 and particularly in the recruitment of tBID and BAX to the mitochondria. [13][14][15][16][17][18][19] Moreover, in type II cells exposed to FASL, it has been suggested that complete activation of caspase 8 is facilitated by the presence of CL in the MOM. 20 In apoptotic conditions, CL becomes peroxidized, and this event is thought to weaken its interaction with cyt c, thus facilitating cyt c release after MOMP.…”

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confidence: 99%

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Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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During apoptosis, proapoptotic BAX and BAK trigger mitochondrial outer membrane (MOM) permeabilization by a mechanism that is not yet fully understood. BH3-only proteins such as tBID, together with lipids of the MOM, are thought to play a key role in BAX and BAK activation. In particular, cardiolipin (CL) has been shown to stimulate tBID-induced BAX activation in vitro. However, it is still unclear whether this process also relies on CL in the cell, or whether it is more dependent on MTCH2, a proposed receptor for tBID present in the MOM. To address this issue, we deleted both alleles of cardiolipin synthase in human HCT116 cells by homologous recombination, which resulted in a complete absence of CL. The CL-deficient cells were fully viable in glucose but displayed impaired oxidative phosphorylation and an inability to grow in galactose. Using these cells, we found that CL was not required for either tBID-induced BAX activation, or for apoptosis in response to treatment with TRAIL. Downregulation of MTCH2 in HCT116 cells also failed to prevent recruitment of tBID to mitochondria in apoptotic conditions. However, when both CL and MTCH2 were depleted, a significant reduction in tBID recruitment was observed, suggesting that in HCT116 cells, CL and MTCH2 can have redundant functions in this process.

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Section: Discussionmentioning

confidence: 95%

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confidence: 99%

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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“…Though both Bax and Drp1 translocate to discrete foci on the mitochondria, studies showed that mitochondrial Bax participates in apoptotic fragmentation of mitochondria by stabilizing Drp1 52, 53, 54. Mitochondrial Drp1 promotes Bax oligomerization and leads to cytochrome C release from mitochondria 55. Therefore, we used the mitochondrial division inhibitor mdivi‐1, which is known to selectively inhibit mitochondrial fission by Drp1 (18).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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BackgroundDesmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown.Methods and ResultsCardiomyocyte‐specific overexpression of mutated desmin (a 7 amino acid deletion R172‐E178, D7‐Des Tg) causes accumulations of electron‐dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7‐Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7‐Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi‐1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7‐Des overexpression in cardiomyocytes.ConclusionsAberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7‐Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy‐associated cellular dysfunction.

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“…99,[102][103][104] However, Kushnareva et al 95 found no evidence supporting a role for these proteins in Bax-induced permeabilization of isolated MOM vesicles. Chemical compounds (mDivi-1 analogs) that had been shown to inhibit Drp1's yeast ortholog, Dnm1, also inhibit MOMP in mammalian cells, 105 and some mDivi-1 analogs blocked BAX-induced pore formation in rat liver and Xenopus MOM vesicles.…”

Section: Bax Monomers Are a Driving Force For Membrane Perturbationmentioning

confidence: 99%

“…Several reports have argued that curvature stress is the ultimate mechanism promoting the formation of protein-conducting membrane pores, and quite possibly the process can involve a cooperation between protein and lipid components to sculpt the membrane. 94,[96][97][98][99][100] Indeed, in cryo-EM images, Bax-induced pores in liposomes 92 and MOM vesicles (Kuwana and Newmeyer, personal This strongly suggests a pore formation or enlargement mechanism involving curvature stress. An alternative model was proposed by Martinez et al 101 after observing a BAX-dependent stepwise opening of highconductance membrane channels.…”

Section: Bax Monomers Are a Driving Force For Membrane Perturbationmentioning

confidence: 99%

The rheostat in the membrane: BCL-2 family proteins and apoptosis

et al. 2013

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Apoptosis, a mechanism for programmed cell death, has key roles in human health and disease. Many signals for cellular life and death are regulated by the BCL-2 family proteins and converge at mitochondria, where cell fate is ultimately decided. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX, BAK) proteins. Previously, it was thought that a balance between these opposing proteins, like a simple 'rheostat', could control the sensitivity of cells to apoptotic stresses. Later, this rheostat concept had to be extended, when it became clear that BCL-2 family proteins regulate each other through a complex network of bimolecular interactions, some transient and some relatively stable. Now, studies have shown that the apoptotic circuitry is even more sophisticated, in that BCL-2 family interactions are spatially dynamic, even in nonapoptotic cells. For example, BAX and BCL-XL can shuttle between the cytoplasm and the mitochondrial outer membrane (MOM). Upstream signaling pathways can regulate the cytoplasmic-MOM equilibrium of BAX and thereby adjust the sensitivity of cells to apoptotic stimuli. Thus, we can view the MOM as the central locale of a dynamic life-death rheostat. BAX invariably forms extensive homo-oligomers after activation in membranes. However, recent studies, showing that activated BAX monomers determine the kinetics of MOM permeabilization (MOMP), perturb the lipid bilayer and form nanometer size pores, pose questions about the role of the oligomerization. Other lingering questions concern the molecular mechanisms of BAX redistribution between MOM and cytoplasm and the details of BAX/BAK-membrane assemblies. Future studies need to delineate how BCL-2 family proteins regulate MOMP, in concert with auxiliary MOM proteins, in a dynamic membrane environment. Technologies aimed at elucidating the structure and function of the full-length proteins in membranes are needed to illuminate some of these critical issues.

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Membrane Remodeling Induced by the Dynamin-Related Protein Drp1 Stimulates Bax Oligomerization

Cited by 372 publications

References 54 publications

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

The rheostat in the membrane: BCL-2 family proteins and apoptosis

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