Bcl-xL increases mitochondrial fission, fusion, and biomass in neurons

Berman, Sarah B.; Chen, Ying-Bei; Qi, Bing; McCaffery, J. Michael; Goebbels, Sandra; Nave, Klaus Armin; Arnold, Beth; Jonas, Elizabeth A.; Pineda, Fernando; Hardwick, J. Marie

doi:10.1083/jcb.200809060

Cited by 206 publications

(219 citation statements)

References 72 publications

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“…BAX, for example, appears to have a different physiological role in regulating mitochondrial dynamics in healthy cells that is separate from its pro-apoptotic function (Karbowski et al, 2006). A similar, but contrary, role has been reported for anti-apoptotic members of the Bcl-2 family of proteins, such as BCL-x L (Berman et al, 2009). Nonetheless, the relationship between the apoptosis program and mitochondrial dynamics is still subject to investigation.…”

Section: Introductionmentioning

confidence: 99%

“…To determine whether the changes in mitochondrial length observed after treatment with low K ϩ and in Bax knock-out mice are associated with changes in individual mitochondrial mass, we next studied the influence of NP1, BAX, and neuronal activity on mitochondrial mass, an index integrating mitochondrial fission, fusion, biogenesis, and degradation (Berman et al, 2009). Consistent with the results observed for mitochondrial length, treatment of wild-type CGNs with low potassium caused a marked reduction of mitochondrial mass, and this effect was prevented by NP1 knockdown (Fig.…”

Section: Np1 Cooperates With Bax In the Regulation Of Mitochondrial Lmentioning

confidence: 99%

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NP1 Regulates Neuronal Activity-Dependent Accumulation of BAX in Mitochondria and Mitochondrial Dynamics

Clayton¹,

Podlesniy²,

Figueiro-Silva³

et al. 2012

J. Neurosci.

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In cultured cerebellar granule neurons, low neuronal activity triggers the intrinsic program of apoptosis, which requires protein synthesis-dependent BAX translocation to mitochondria, a process that may underlie neuronal damage in neurodegeneration. However, the mechanisms that link neuronal activity with the induction of the mitochondrial program of apoptosis remain unclear. Neuronal pentraxin 1 (NP1) is a pro-apoptotic protein induced by low neuronal activity that is increased in damaged neurites in Alzheimer's disease-affected brains. Here we report that NP1 facilitates the accumulation of BAX in mitochondria and regulates mitochondrial dynamics during apoptosis in rat and mouse cerebellar granule neurons in culture. Reduction of neuronal activity increases NP1 protein levels in mitochondria and contributes to mitochondrial fragmentation in a Bax-dependent manner. In addition, NP1 is involved in mitochondrial transport in healthy neurons. These results show that NP1 is targeted to mitochondria acting upstream of BAX and uncover a novel function for NP1 in the regulation of mitochondrial dynamics and trafficking during apoptotic neurodegeneration.

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Section: Introductionmentioning

confidence: 99%

Section: Np1 Cooperates With Bax In the Regulation Of Mitochondrial Lmentioning

confidence: 99%

NP1 Regulates Neuronal Activity-Dependent Accumulation of BAX in Mitochondria and Mitochondrial Dynamics

Clayton¹,

Podlesniy²,

Figueiro-Silva³

et al. 2012

J. Neurosci.

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“…In live imaging studies, a population of relatively small axonal mitochondria is translocated in anterograde and retrograde directions (17,18,20). Motile mitochondria are made in the neuronal cell body, can transiently stop within stationary sites, and can fuse with or bud from stationary mitochondria; they are essential for axonal mitochondria turnover and redistribution (20)(21)(22)(23). Transport and docking of axonal mitochondria are dynamic processes that can be modulated by axonal metabolic demands.…”

mentioning

confidence: 99%

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Ohno

Hao

Mahad

et al. 2014

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

110

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Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na + channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.A xonal loss is the major cause of permanent neurological disability in individuals with primary diseases of myelin (1). Axonal degeneration associated with myelin diseases has been well studied in the immune-mediated CNS demyelinating disease multiple sclerosis. Two mechanisms are responsible for the degeneration of demyelinated axons in multiple sclerosis brains. First, axons are transected in acute multiple sclerosis lesions (2) and axonal injury correlates with the number of infiltrating peripheral immune cells (3, 4). Edema associated with breakdown of the blood-brain barrier and toxic substances secreted by inflammatory immune cells are thought to transect the acutely demyelinated axon (5). Second, chronically demyelinated axons degenerate as a result of loss of trophic support provided by oligodendrocytes and myelin (6, 7). In addition to increasing the speed of nerve transmission, oligodendrocytes and myelin provide axons with trophic support that is essential for their longterm survival (8-10). Although most demyelinated axons compensate for loss of oligodendrocytes/myelin, additional insults to axonal mitochondria impair axonal metabolism, increase axonal Ca 2+ , and promote progressive disruption of mitochondrial function (11,12). Changes in axonal mitochondria have been described in chronically demyelinated axons in postmortem multiple sclerosis tissue, and include decreased expression of nuclear-encoded mitochondrial genes (13), reduced mitochondrial respiration (14), and genetic alterations in mitochondrial DNA (15). A vicious cycle of reduced ATP production and increased axonal Ca 2+ results in degeneration of the chronically demyelinated axon.Myelinated axons contain two populations of mitochondria. Most axonal mitochondria do not appear to translocate and are located at...

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“…Mitochondrial Bax and Bcl-x L seem to be involved in the regulation of mitochondrial morphology, [16][17][18] and Bax has been shown to promote the assembly of the GTPase mitofusin 2 (Mfn2). 16,17 Mfn2 is one of two large GTPases that mediate OMM fusion.…”

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confidence: 99%

The C-terminal helix of Bcl-xL mediates Bax retrotranslocation from the mitochondria

et al. 2012

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The proapoptotic Bcl-2 protein Bax can commit a cell to apoptosis by translocation from the cytosol to the mitochondria and permeabilization of the outer mitochondrial membrane. Prosurvival Bcl-2 family members, such as Bcl-x L , control Bax activity. Bcl-x L recognizes Bax after a conformational change in the N-terminal segment of Bax on the mitochondria and retrotranslocates it back into the cytoplasm, stabilizing the inactive form of Bax. Here we show that Bax retrotranslocation depends on the C-terminal helix of Bcl-x L . Deletion or substitution of this segment reduces Bax retrotranslocation and correlates with the accumulation of GFP-tagged or endogenous Bax on the mitochondria of non-apoptotic cells. Unexpectedly, the substitution of the Bcl-x L membrane anchor by the corresponding Bax segment reverses the Bax retrotranslocation activity of Bcl-x L , but not that of Bcl-x L shuttling. Bax retrotranslocation depends on interaction to the Bcl-x L membrane anchor and interaction between the Bax BH3 domain and the Bcl-x L hydrophobic cleft. Interference with either interaction increases mitochondrial levels of endogenous Bax. In healthy cells, mitochondrial Bax does not permeabilize the outer mitochondrial membrane, but increases cell death after apoptosis induction.

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Bcl-xL increases mitochondrial fission, fusion, and biomass in neurons

Cited by 206 publications

References 72 publications

NP1 Regulates Neuronal Activity-Dependent Accumulation of BAX in Mitochondria and Mitochondrial Dynamics

NP1 Regulates Neuronal Activity-Dependent Accumulation of BAX in Mitochondria and Mitochondrial Dynamics

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

The C-terminal helix of Bcl-xL mediates Bax retrotranslocation from the mitochondria

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