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Article: Clearing the brain's cobwebs: the role of autophagy in neuroprotection.

Bossy, Blaise / Perkins, Guy / Bossy-Wetzel, Ella

2009 Volume 6, Issue 2, Page(s) 97–101

Abstract: Protein aggregates or inclusion bodies are common hallmarks of age-related neurodegenerative disorders. Why these aggregates form remains unclear. Equally debated is whether they are toxic, protective, or simple by-products. Increasing evidence, however, ...

Abstract	Protein aggregates or inclusion bodies are common hallmarks of age-related neurodegenerative disorders. Why these aggregates form remains unclear. Equally debated is whether they are toxic, protective, or simple by-products. Increasing evidence, however, supports the notion that in general aggregates confer toxicity and disturb neuronal function by hampering axonal transport, synaptic integrity, transcriptional regulation, and mitochondrial function. Thus, neuroscientists in search of effective treatments to slow neural loss during neurodegeneration have long been interested in finding new ways to clear inclusion bodies. Intriguingly, two studies using conditional neuron-specific gene ablations of autophagy regulators in mice revealed that autophagy loss elicits inclusion body formation and a neurodegenerative cascade.Such studies indicate autophagy may be a built-in defense mechanism to clear the nervous system of inclusion bodies.This new finding has implications for our understanding of aging and neurodegeneration and the development of new therapies. First, we discuss the pathways underlying autophagy and its controversial role in cell death and survival regulation.We then discuss the physiological role of autophagy in the aging process of the nervous system. In the final portion of this review, we discuss the therapeutic promise of inducing autophagy and the potential side effects of such treatments.
Language	English
Publishing date	2009-03-05
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2192352-8
ISSN	1875-6190 ; 1570-159X
ISSN (online)	1875-6190
ISSN	1570-159X
DOI	10.2174/157015908784533897
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Article: SOD1 Lysine 123 Acetylation in the Adult Central Nervous System.

Kaliszewski, Michael / Kennedy, Austin K / Blaes, Shelby L / Shaffer, Robert S / Knott, Andrew B / Song, Wenjun / Hauser, Henry A / Bossy, Blaise / Huang, Ting-Ting / Bossy-Wetzel, Ella

Frontiers in cellular neuroscience

2016 Volume 10, Page(s) 287

Abstract: Superoxide dismutase 1 (SOD1) knockout ( ...

Abstract	Superoxide dismutase 1 (SOD1) knockout (
Language	English
Publishing date	2016-12-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2016.00287
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Article ; Online: Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1α.

Song, Wenjun / Song, Yuting / Kincaid, Brad / Bossy, Blaise / Bossy-Wetzel, Ella

Neurobiology of disease

2012 Volume 51, Page(s) 72–81

Abstract: Mutations in the Cu/Zn Superoxide Dismutase (SOD1) gene cause an inherited form of ALS with upper and lower motor neuron loss. The mechanism underlying mutant SOD1-mediated motor neuron degeneration remains unclear. While defects in mitochondrial ... ...

Abstract	Mutations in the Cu/Zn Superoxide Dismutase (SOD1) gene cause an inherited form of ALS with upper and lower motor neuron loss. The mechanism underlying mutant SOD1-mediated motor neuron degeneration remains unclear. While defects in mitochondrial dynamics contribute to neurodegeneration, including ALS, previous reports remain conflicted. Here, we report an improved technique to isolate, transfect, and culture rat spinal cord motor neurons. Using this improved system, we demonstrate that mutant SOD1(G93A) triggers a significant decrease in mitochondrial length and an accumulation of round fragmented mitochondria. The increase of fragmented mitochondria coincides with an arrest in both anterograde and retrograde axonal transport and increased cell death. In addition, mutant SOD1(G93A) induces a reduction in neurite length and branching that is accompanied with an abnormal accumulation of round mitochondria in growth cones. Furthermore, restoration of the mitochondrial fission and fusion balance by dominant-negative dynamin-related protein 1 (DRP1) expression rescues the mutant SOD1(G93A)-induced defects in mitochondrial morphology, dynamics, and cell viability. Interestingly, both SIRT3 and PGC-1α protect against mitochondrial fragmentation and neuronal cell death by mutant SOD1(G93A). This data suggests that impairment in mitochondrial dynamics participates in ALS and restoring this defect might provide protection against mutant SOD1(G93A)-induced neuronal injury.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Axonal Transport/genetics ; Disease Models, Animal ; Dynamins/metabolism ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Dynamics/physiology ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Mutation ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; RNA-Binding Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; Sirtuin 3/metabolism ; Spinal Cord/metabolism ; Spinal Cord/pathology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transcription Factors/metabolism ; Transfection
Chemical Substances	Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Ppargc1a protein, rat ; RNA-Binding Proteins ; Transcription Factors ; Sod1 protein, mouse (EC 1.15.1.1) ; Sod1 protein, rat (EC 1.15.1.1) ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; Sirtuin 3 (EC 3.5.1.-) ; Dnm1l protein, rat (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2012-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2012.07.004
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Article ; Online: Molecular mechanism of DRP1 assembly studied in vitro by cryo-electron microscopy.

Basu, Kaustuv / Lajoie, Driss / Aumentado-Armstrong, Tristan / Chen, Jin / Koning, Roman I / Bossy, Blaise / Bostina, Mihnea / Sik, Attila / Bossy-Wetzel, Ella / Rouiller, Isabelle

PloS one

2017 Volume 12, Issue 6, Page(s) e0179397

Abstract: Mitochondria are dynamic organelles that continually adapt their morphology by fusion and fission events. An imbalance between fusion and fission has been linked to major neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's ... ...

Abstract	Mitochondria are dynamic organelles that continually adapt their morphology by fusion and fission events. An imbalance between fusion and fission has been linked to major neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's diseases. A member of the Dynamin superfamily, dynamin-related protein 1 (DRP1), a dynamin-related GTPase, is required for mitochondrial membrane fission. Self-assembly of DRP1 into oligomers in a GTP-dependent manner likely drives the division process. We show here that DRP1 self-assembles in two ways: i) in the presence of the non-hydrolysable GTP analog GMP-PNP into spiral-like structures of ~36 nm diameter; and ii) in the presence of GTP into rings composed of 13-18 monomers. The most abundant rings were composed of 16 monomers and had an outer and inner ring diameter of ~30 nm and ~20 nm, respectively. Three-dimensional analysis was performed with rings containing 16 monomers. The single-particle cryo-electron microscopy map of the 16 monomer DRP1 rings suggests a side-by-side assembly of the monomer with the membrane in a parallel fashion. The inner ring diameter of 20 nm is insufficient to allow four membranes to exist as separate entities. Furthermore, we observed that mitochondria were tubulated upon incubation with DRP1 protein in vitro. The tubes had a diameter of ~ 30nm and were decorated with protein densities. These findings suggest DRP1 tubulates mitochondria, and that additional steps may be required for final mitochondrial fission.
MeSH term(s)	Cryoelectron Microscopy ; GTP Phosphohydrolases/chemistry ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Guanosine Triphosphate/chemistry ; Guanosine Triphosphate/metabolism ; Humans ; Microtubule-Associated Proteins/chemistry ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins/chemistry ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Protein Binding ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Protein Structure, Quaternary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification
Chemical Substances	Microtubule-Associated Proteins ; Mitochondrial Proteins ; Protein Isoforms ; Recombinant Proteins ; Guanosine Triphosphate (86-01-1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5)
Language	English
Publishing date	2017-06-20
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0179397
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Article ; Online: Molecular mechanism of DRP1 assembly studied in vitro by cryo-electron microscopy.

Kaustuv Basu / Driss Lajoie / Tristan Aumentado-Armstrong / Jin Chen / Roman I Koning / Blaise Bossy / Mihnea Bostina / Attila Sik / Ella Bossy-Wetzel / Isabelle Rouiller

PLoS ONE, Vol 12, Iss 6, p e

2017 Volume 0179397

Abstract	Mitochondria are dynamic organelles that continually adapt their morphology by fusion and fission events. An imbalance between fusion and fission has been linked to major neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's diseases. A member of the Dynamin superfamily, dynamin-related protein 1 (DRP1), a dynamin-related GTPase, is required for mitochondrial membrane fission. Self-assembly of DRP1 into oligomers in a GTP-dependent manner likely drives the division process. We show here that DRP1 self-assembles in two ways: i) in the presence of the non-hydrolysable GTP analog GMP-PNP into spiral-like structures of ~36 nm diameter; and ii) in the presence of GTP into rings composed of 13-18 monomers. The most abundant rings were composed of 16 monomers and had an outer and inner ring diameter of ~30 nm and ~20 nm, respectively. Three-dimensional analysis was performed with rings containing 16 monomers. The single-particle cryo-electron microscopy map of the 16 monomer DRP1 rings suggests a side-by-side assembly of the monomer with the membrane in a parallel fashion. The inner ring diameter of 20 nm is insufficient to allow four membranes to exist as separate entities. Furthermore, we observed that mitochondria were tubulated upon incubation with DRP1 protein in vitro. The tubes had a diameter of ~ 30nm and were decorated with protein densities. These findings suggest DRP1 tubulates mitochondria, and that additional steps may be required for final mitochondrial fission.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Assessing mitochondrial morphology and dynamics using fluorescence wide-field microscopy and 3D image processing.

Song, Wenjun / Bossy, Blaise / Martin, Ola J / Hicks, Andrew / Lubitz, Sarah / Knott, Andrew B / Bossy-Wetzel, Ella

Methods (San Diego, Calif.)

2008 Volume 46, Issue 4, Page(s) 295–303

Abstract: Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microscopy and 3D imaging ... ...

Abstract	Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microscopy and 3D imaging techniques to assess mitochondrial shape, number and length in various cell types including cancer cell lines, motor neurons and astrocytes. Furthermore, we illustrate how to assess mitochondrial fission and fusion events by 3D time-lapse imaging and to calculate mitochondrial length and numbers as a function of time. These imaging methods provide useful tools to investigate mitochondrial dynamics in health, aging and disease.
MeSH term(s)	Animals ; Astrocytes/ultrastructure ; HeLa Cells ; Humans ; Image Processing, Computer-Assisted/methods ; Imaging, Three-Dimensional/methods ; Microscopy, Fluorescence/methods ; Mitochondria/physiology ; Mitochondria/ultrastructure ; Mitochondrial Size ; Motor Neurons/ultrastructure ; Rats
Language	English
Publishing date	2008-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2008.10.003
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Article ; Online: S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer's disease.

Bossy, Blaise / Petrilli, Alejandra / Klinglmayr, Eva / Chen, Jin / Lütz-Meindl, Ursula / Knott, Andrew B / Masliah, Eliezer / Schwarzenbacher, Robert / Bossy-Wetzel, Ella

Journal of Alzheimer's disease : JAD

2010 Volume 20 Suppl 2, Page(s) S513–26

Abstract: Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer's disease (AD) and might play a causative role in disease onset and progression. The underlying mechanisms of mitochondrial and synaptic dysfunction in AD ... ...

Abstract	Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer's disease (AD) and might play a causative role in disease onset and progression. The underlying mechanisms of mitochondrial and synaptic dysfunction in AD remain unclear. We previously reported that nitric oxide (NO) triggers persistent mitochondrial fission and causes neuronal cell death. A recent article claimed that S-nitrosylation of dynamin related protein 1 (DRP1) at cysteine 644 causes protein dimerization and increased GTPase activity and is the mechanism responsible for NO-induced mitochondrial fission and neuronal injury in AD, but not in Parkinson's disease (PD). However, this report remains controversial. To resolve the controversy, we investigated the effects of S-nitrosylation on DRP1 structure and function. Contrary to the previous report, S-nitrosylation of DRP1 does not increase GTPase activity or cause dimerization. In fact, DRP1 does not exist as a dimer under native conditions, but rather as a tetramer capable of self-assembly into higher order spiral- and ring-like oligomeric structures after nucleotide binding. S-nitrosylation, as confirmed by the biotin-switch assay, has no impact on DRP1 oligomerization. Importantly, we found no significant difference in S-nitrosylated DRP1 (SNO-DRP1) levels in brains of age-matched normal, AD, or PD patients. We also found that S-nitrosylation is not specific to DRP1 because S-nitrosylated optic atrophy 1 (SNO-OPA1) is present at comparable levels in all human brain samples. Finally, we show that NO triggers DRP1 phosphorylation at serine 616, which results in its activation and recruitment to mitochondria. Our data indicate the mechanism underlying nitrosative stress-induced mitochondrial fragmentation in AD is not DRP1 S-nitrosylation.
MeSH term(s)	Aging/pathology ; Alzheimer Disease/enzymology ; Alzheimer Disease/etiology ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Biotin/metabolism ; Brain/enzymology ; Brain/ultrastructure ; Cell Line, Transformed ; Cysteine/genetics ; Cysteine/metabolism ; Dithiothreitol/pharmacology ; Dynamins ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Humans ; Microscopy, Electron, Transmission/methods ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondrial Diseases/complications ; Mitochondrial Diseases/enzymology ; Mitochondrial Proteins/drug effects ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Postmortem Changes ; Protein Multimerization/drug effects ; Protein Multimerization/physiology
Chemical Substances	Microtubule-Associated Proteins ; Mitochondrial Proteins ; Biotin (6SO6U10H04) ; GTP Phosphohydrolases (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5) ; Cysteine (K848JZ4886) ; Dithiothreitol (T8ID5YZU6Y)
Language	English
Publishing date	2010-05-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-2010-100552
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Article ; Online: Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.

Song, Wenjun / Chen, Jin / Petrilli, Alejandra / Liot, Geraldine / Klinglmayr, Eva / Zhou, Yue / Poquiz, Patrick / Tjong, Jonathan / Pouladi, Mahmoud A / Hayden, Michael R / Masliah, Eliezer / Ellisman, Mark / Rouiller, Isabelle / Schwarzenbacher, Robert / Bossy, Blaise / Perkins, Guy / Bossy-Wetzel, Ella

Nature medicine

2011 Volume 17, Issue 3, Page(s) 377–382

Abstract: Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing ... ...

Abstract	Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.
MeSH term(s)	Animals ; Disease Models, Animal ; Dynamins ; GTP Phosphohydrolases/metabolism ; Humans ; Huntingtin Protein ; Mice ; Microtubule-Associated Proteins/metabolism ; Mitochondria/enzymology ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Binding
Chemical Substances	HTT protein, human ; Huntingtin Protein ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; Nerve Tissue Proteins ; Nuclear Proteins ; GTP Phosphohydrolases (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2011-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.2313
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Article ; Online: Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons.

Li, Hongmei / Chen, Yingbei / Jones, Adrienne F / Sanger, Richard H / Collis, Leon P / Flannery, Richard / McNay, Ewan C / Yu, Tingxi / Schwarzenbacher, Robert / Bossy, Blaise / Bossy-Wetzel, Ella / Bennett, Michael V L / Pypaert, Marc / Hickman, John A / Smith, Peter J S / Hardwick, J Marie / Jonas, Elizabeth A

Proceedings of the National Academy of Sciences of the United States of America

2008 Volume 105, Issue 6, Page(s) 2169–2174

Abstract: Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL ... ...

Abstract	Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-xL, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-xL or inhibiting it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-xL appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-xL coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-xL protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-xL positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.
MeSH term(s)	Animals ; Cells, Cultured ; Dynamins/physiology ; Hippocampus/cytology ; Hippocampus/metabolism ; Mitochondria/metabolism ; Rats ; Synapses ; Synaptic Transmission ; bcl-X Protein/physiology
Chemical Substances	bcl-X Protein ; Dnm1l protein, rat (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2008-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0711647105
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Article: Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons.

Barsoum, Mark J / Yuan, Hua / Gerencser, Akos A / Liot, Géraldine / Kushnareva, Yulia / Gräber, Simone / Kovacs, Imre / Lee, Wilson D / Waggoner, Jenna / Cui, Jiankun / White, Andrew D / Bossy, Blaise / Martinou, Jean-Claude / Youle, Richard J / Lipton, Stuart A / Ellisman, Mark H / Perkins, Guy A / Bossy-Wetzel, Ella

The EMBO journal

2006 Volume 25, Issue 16, Page(s) 3900–3911

Abstract: Mitochondria are present as tubular organelles in neuronal projections. Here, we report that mitochondria undergo profound fission in response to nitric oxide (NO) in cortical neurons of primary cultures. Mitochondrial fission by NO occurs long before ... ...

Abstract	Mitochondria are present as tubular organelles in neuronal projections. Here, we report that mitochondria undergo profound fission in response to nitric oxide (NO) in cortical neurons of primary cultures. Mitochondrial fission by NO occurs long before neurite injury and neuronal cell death. Furthermore, fission is accompanied by ultrastructural damage of mitochondria, autophagy, ATP decline and generation of free radicals. Fission is occasionally asymmetric and can be reversible. Strikingly, mitochondrial fission is also an early event in ischemic stroke in vivo. Mitofusin 1 (Mfn1) or dominant-negative Dynamin related protein 1 (Drp1(K38A)) inhibits mitochondrial fission induced by NO, rotenone and Amyloid-beta peptide. Conversely, overexpression of Drp1 or Fis1 elicits fission and increases neuronal loss. Importantly, NO-induced neuronal cell death was mitigated by Mfn1 and Drp1(K38A). Thus, persistent mitochondrial fission may play a causal role in NO-mediated neurotoxicity.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Amyloid beta-Peptides/pharmacology ; Animals ; Autophagy ; Cells, Cultured ; Cerebral Cortex/cytology ; Dynamins/physiology ; Energy Metabolism ; Free Radicals/metabolism ; GTP Phosphohydrolases/physiology ; Membrane Proteins/physiology ; Microscopy, Electron, Transmission ; Mitochondria/drug effects ; Mitochondria/ultrastructure ; Mitochondrial Proteins/physiology ; Neurons/ultrastructure ; Nitric Oxide/physiology ; Peptide Fragments/pharmacology ; Rats ; Rotenone/pharmacology ; Stroke/metabolism ; Stroke/pathology
Chemical Substances	Amyloid beta-Peptides ; Free Radicals ; Membrane Proteins ; Mfn1 protein, rat ; Mitochondrial Proteins ; Peptide Fragments ; Rotenone (03L9OT429T) ; Nitric Oxide (31C4KY9ESH) ; Adenosine Triphosphate (8L70Q75FXE) ; GTP Phosphohydrolases (EC 3.6.1.-) ; Mfn1 protein, mouse (EC 3.6.1.-) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2006-07-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/sj.emboj.7601253
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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito