Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins

Brooks, Craig R.; Wei, Qingqing; Feng, Leping; Dong, Guie; Tao, Yanmei; Mei, Lin; Xie, Zili; Dong, Zheng

doi:10.1073/pnas.0703976104

Cited by 311 publications

(346 citation statements)

References 46 publications

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“…However, the mechanism by which they induce apoptosis may differ. It has been previously shown that BAK, but not BAX, plays an important role in mitochondrial fragmentation, a morphological change that facilitates MOMP during apoptosis (35). Here we describe a second unique function for BAK in apoptosis, namely regulation of ceramide generation.…”

Section: Discussionmentioning

confidence: 79%

“…Furthermore, ceramides induce negative curvature and lateral phase separation in giant liposomes leading to their fragmentation (45). Thus, ceramide generation may change membrane curvature to facilitate BAK-induced mitochondrial fragmentation in parallel with the inhibition of mitochondrial fusion machinery as has been previously described (35).…”

Section: Discussionmentioning

confidence: 96%

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The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Siskind

Mullen

Rosales

et al. 2010

Journal of Biological Chemistry

113

103

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The BCL-2 family members BAK and BAX are required for apoptosis and trigger mitochondrial outer membrane permeabilization (MOMP). Here we identify a MOMP-independent function of BAK as a required factor for long-chain ceramide production in response to pro-apoptotic stress. UV-C irradiation of wild-type (WT) cells increased long-chain ceramides; blocking ceramide generation prevented caspase activation and cell death, demonstrating that long-chain ceramides play a key role in UV-C-induced apoptosis. In contrast, UV-C irradiation did not increase long-chain ceramides in BAK and BAX double knock-out cells. Notably, this was not specific to the cell type (baby mouse kidney cells, hematopoietic) nor the apoptotic stimulus employed (UV-C, cisplatin, and growth factor withdrawal). Importantly, long-chain ceramide generation was dependent on the presence of BAK, but not BAX. However, ceramide generation was independent of the known downstream actions of BAK in apoptosis (MOMP or caspase activation), suggesting a novel role for BAK in apoptosis. Finally, enzymatic assays identified ceramide synthase as the mechanism by which BAK regulates ceramide metabolism. There was no change in CerS expression at the message or protein level, indicating regulation at the post-translational level. Moreover, CerS activity in BAK KO microsomes can be reactivated upon addition of BAKcontaining microsomes. The data presented indicate that ceramide-induced apoptosis is dependent upon BAK and identify a novel role for BAK during apoptosis. By establishing a unique role for BAK in long-chain ceramide metabolism, these studies further demonstrate that the seemingly redundant proteins BAK and BAX have distinct mechanisms of action during apoptosis induction.Programmed cell death (apoptosis) is a complex, multistep process essential for normal tissue homeostasis and development. A key event in apoptotic signaling is mitochondrial outer membrane permeabilization (MOMP), 3 whereby pro-apoptotic factors are released from the mitochondrial intermembrane space into the cytosol resulting in the activation of caspases and triggering the execution phase of apoptosis. Multiple cell death pathways converge on MOMP, and it is considered a necessary step for the commitment of cells to apoptosis. Anti-apoptotic BCL-2 proteins like BCL-2 and BCL-X L can block MOMP and cell death when overexpressed. On the other hand, the proapoptotic BCL-2 proteins BAK and BAX are necessary for MOMP in response to a wide variety of death-inducing signals. In fact, cells lacking both BAK and BAX are highly resistant to apoptotic stimuli (1-4).Sphingolipids have been extensively implicated in the apoptotic response. Ceramide, a central molecule of sphingolipid metabolism, has been shown to be involved in programmed cell death through several lines of evidence. First, cellular levels of ceramide are elevated by a variety of apoptotic stimuli. Second, blocking ceramide generation delays or abrogates cell death in response to many different signals (5-9). Moreover, cancer cells ...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 96%

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Siskind

Mullen

Rosales

et al. 2010

Journal of Biological Chemistry

113

103

View full text Add to dashboard Cite

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“…Other groups reported similar findings, while ablation of Drp1 was also shown to reduce cytochrome c release (Breckenridge et al, 2003;Brooks et al, 2007;Germain et al, 2005;Lee et al, 2004;Neuspiel et al, 2005). The role of mitochondrial fragmentation in the progression of apoptosis has also been investigated by inhibiting fission through enforced fusion.…”

Section: Accepted M Manuscriptmentioning

confidence: 84%

“…Bak has been shown to interact with Mfn1 and Mfn2, while Bax promotes the activity of Mfn2 (Brooks et al, 2007, Karbowski et al, 2006. In addition, Bcl-2 family members may interact with other cellular proteins that modulate mitochondrial morphology and distribution within the cell.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Mitochondrial fission/fusion dynamics and apoptosis

2010

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Mitochondria play an important role in the progression of apoptosis through the release of pro-apoptotic factors, such as cytochrome c, from the mitochondrial intermembrane space.During this process, mitochondrial networks are dramatically reorganised from long filamentous interconnected tubules into small punctate spheres. Whether remodelling of mitochondrial networks is necessary for apoptosis-associated cytochrome c release, or merely an accompanying process, has been a subject of debate. Here we discuss evidence for and against the role of mitochondrial fragmentation in the progression of apoptosis and highlight recent advances which indicate that mitochondrial fission is not a critical requirement for apoptosis-associated cytochrome c release. We also discuss an emerging role for Bcl-2 family members as regulators of mitochondrial fission and fusion dynamics, independent of the role of this family in the regulation of apoptosis.

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“…However, recent studies suggest that Bak acts upstream of Bax in promoting mitochondrial apoptosis (25,45), and that Bak plays the central role in apoptosis of differentiated neurons (24). Moreover, Bak may play an exclusive role in oxidative stress-mediated apoptosis in the brain (25), and also in mitochondrial fragmentation (45).…”

Section: Discussionmentioning

confidence: 99%

Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

Someya

Kondo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

285

304

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Age-related hearing loss (AHL), known as presbycusis, is a universal feature of mammalian aging and is the most common sensory disorder in the elderly population. The molecular mechanisms underlying AHL are unknown, and currently there is no treatment for the disorder. Here we report that C57BL/6J mice with a deletion of the mitochondrial pro-apoptotic gene Bak exhibit reduced age-related apoptotic cell death of spiral ganglion neurons and hair cells in the cochlea, and prevention of AHL. Oxidative stress induces Bak expression in primary cochlear cells, and Bak deficiency prevents apoptotic cell death. Furthermore, a mitochondrially targeted catalase transgene suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Oral supplementation with the mitochondrial antioxidants ␣-lipoic acid and coenzyme Q 10 also suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Thus, induction of a Bak-dependent mitochondrial apoptosis program in response to oxidative stress is a key mechanism of AHL in C57BL/6J mice.aging ͉ antioxidant ͉ cochlea ͉ oxidative stress ͉ presbycusis A ge-related hearing loss (AHL), also known as presbycusis, is characterized by an age-dependent decline of auditory function associated with loss of sensory hair cells, spiral ganglion (SG) neurons, and stria vascularis cells in the cochlea of the inner ear (1, 2). Hair cells and SG neurons do not regenerate in mammals, and loss of these long-lived cochlear cells leads to permanent hearing impairment. AHL affects more than 40% of people greater than 65 years of age in the United States (1, 2) and is projected to afflict more than 28 million Americans by 2030 (1, 3

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Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins

Cited by 311 publications

References 46 publications

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

The BCL-2 Protein BAK Is Required for Long-chain Ceramide Generation during Apoptosis

Mitochondrial fission/fusion dynamics and apoptosis

Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

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