Bax Forms Two Types of Channels, One of Which Is Voltage-Gated

Lin, Shang H.; Perera, Meenu N.; Nguyen, Toan; Datskovskiy, Debra; Miles, Megan; Colombini, Marco

doi:10.1016/j.bpj.2011.09.041

Cited by 21 publications

(18 citation statements)

References 45 publications

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“…Bax has been shown to adopt two types of channel activities, one of which has a small pore size (0.9 nm) and is homogenous in the outer mitochondrial membrane, which could fulfill the permeability function we observed here to permit nonapoptotic cell death (Lin et al, 2011). As another consideration, the α5/α6 domain of Bax is known to have membrane permeation activity and to permit pore formation on its own, the permeation size of which appears to reach an equilibrium of less than 10 kDa (Fuertes et al, 2010).…”

Section: Discussionmentioning

confidence: 54%

Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

Karch

Kwong

Burr

et al. 2013

eLife

237

247

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A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death.DOI: http://dx.doi.org/10.7554/eLife.00772.001

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Section: Discussionmentioning

confidence: 54%

Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

Karch

Kwong

Burr

et al. 2013

eLife

237

247

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“…39 Indeed, the inactive/passive state of Bax and Bak permitted necrosis by simply changing the physical properties of the outer mitochondrial membrane and making it more permeable and amenable to rupturing following inner mitochondrial membrane opening of the MPTP. 39, 77 Hence, a small increase in permeability created by inactive/passive Bax/Bak as they reside in the outer mitochondrial membrane was required for mitochondrial rupture post MPTP opening to ultimately mediate necrosis (Figure 2). 39 Other notable findings were that the activity of Bax and Bak in the outer mitochondrial membrane were not functionally coupled to the inner membrane, suggesting that the MPTP is not a coordinated activity that directly spans the outer and inner mitochondrial membranes simultaneously.…”

Section: Mptp-dependent Necrosismentioning

confidence: 99%

Regulated Necrotic Cell Death

Karch

Molkentin

2015

Circulation Research

129

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While the molecular effectors of apoptotic cell death have been largely annotated over the past 30 years, leading to a strong biologic understanding of this process and its importance in cell biology, cell death through necrosis has only recently been accepted as a similarly regulated process with definable molecular effectors. The mitochondria are important and central mediators of both apoptosis and regulated necrosis. In apoptosis the Bcl-2 family members Bax and Bak undergo oligomerization in the outer mitochondrial membrane resulting in the release of apoptosis inducing substrates and the activation of caspases and nucleases. In contrast, during necrosis the mitochondria become dysfunctional and maladaptive in conjunction with reactive oxygen species production and the loss of ATP production, in part through opening of the mitochondrial permeability transition pore. While regulated necrosis is caspase independent, recent evidence has shown that it still requires the apoptotic regulators Bax and Bak, which can regulate the permeability characteristics of the outer mitochondrial membrane in their non-oligomerized state. Here we review the non-apoptotic side of Bcl-2 family, specifically the role of Bax and Bak in regulated necrotic cell death. We will also discuss how these Bcl-2 family member effectors could be part of a larger integrated network that ultimately decides the fate of a given cell somewhere within a molecular continuum between apoptosis and regulated necrosis.

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“…However, these are also found in other cell types (e.g. In addition, Bax can also form highly ordered and relatively small voltagegated channels in phospholipid membranes [12]. tonoplasts [5] and mitochondria [7]).…”

Section: Introductionmentioning

confidence: 99%

Bax channel triplet: co-operativity and voltage gating

Lin

Cherian

et al. 2014

Biochemical Journal

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Bax, despite being a cytosolic protein, has the distinct ability to form channels in the mitochondrial outer membrane, which are capable of releasing proteins that initiate the execution phase of apoptosis. When studied in a planar phospholipid membrane system, full-length activated Bax can form conducting entities consistent with linearly organized three-channel units displaying steep voltage-gating (n=14) that rivals that of channels in excitable membranes. In addition, the channels display strong positive co-operativity possibly arising from the charge distribution of the voltage sensors. On the basis of functional behaviour, one of the channels in this functional triplet is oriented in the opposite direction to the others often resulting in conflicts between the effects of the electric field and the positive co-operativity of adjacent channels. The closure of the first channel occurs at positive potentials and this permits the second to close, but at negative potentials. The closure of the second channel in turn permits closure of the third, but at positive potentials. Positive co-operativity manifests itself in a number of ways including the second and the third channels opening virtually simultaneously. This extraordinary behaviour must have important, although as yet undefined, physiological roles.

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Bax Forms Two Types of Channels, One of Which Is Voltage-Gated

Cited by 21 publications

References 45 publications

Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice

Regulated Necrotic Cell Death

Bax channel triplet: co-operativity and voltage gating

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