Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis
While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/61798 |
| _version_ | 1797998471191461888 |
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| author | Sina C Rosenkranz Artem A Shaposhnykov Simone Träger Jan Broder Engler Maarten E Witte Vanessa Roth Vanessa Vieira Nanne Paauw Simone Bauer Celina Schwencke-Westphal Charlotte Schubert Lukas Can Bal Benjamin Schattling Ole Pless Jack van Horssen Marc Freichel Manuel A Friese |
| author_facet | Sina C Rosenkranz Artem A Shaposhnykov Simone Träger Jan Broder Engler Maarten E Witte Vanessa Roth Vanessa Vieira Nanne Paauw Simone Bauer Celina Schwencke-Westphal Charlotte Schubert Lukas Can Bal Benjamin Schattling Ole Pless Jack van Horssen Marc Freichel Manuel A Friese |
| author_sort | Sina C Rosenkranz |
| collection | DOAJ |
| description | While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In mice, neuronal overexpression of Ppargc1a, which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity, and maximum respiratory capacity. Moreover, Ppargc1a-overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Ppargc1a aggravated neurodegeneration during experimental autoimmune encephalomyelitis, while neuronal overexpression of Ppargc1a ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy. |
| first_indexed | 2024-04-11T10:49:14Z |
| format | Article |
| id | doaj.art-d34d7f79b1524923b04c1e6c6a2626e7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:49:14Z |
| publishDate | 2021-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d34d7f79b1524923b04c1e6c6a2626e72022-12-22T04:28:58ZengeLife Sciences Publications LtdeLife2050-084X2021-02-011010.7554/eLife.61798Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosisSina C Rosenkranz0https://orcid.org/0000-0002-5228-4266Artem A Shaposhnykov1https://orcid.org/0000-0001-6772-6074Simone Träger2Jan Broder Engler3https://orcid.org/0000-0002-3169-2076Maarten E Witte4https://orcid.org/0000-0002-1407-6220Vanessa Roth5Vanessa Vieira6https://orcid.org/0000-0002-0205-9669Nanne Paauw7Simone Bauer8Celina Schwencke-Westphal9https://orcid.org/0000-0002-5105-4290Charlotte Schubert10https://orcid.org/0000-0002-2967-4290Lukas Can Bal11https://orcid.org/0000-0003-4731-2311Benjamin Schattling12https://orcid.org/0000-0001-8809-9073Ole Pless13https://orcid.org/0000-0002-1468-316XJack van Horssen14https://orcid.org/0000-0003-4078-7402Marc Freichel15https://orcid.org/0000-0003-1387-2636Manuel A Friese16https://orcid.org/0000-0001-6380-2420Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands; Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, NetherlandsInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, NetherlandsInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyFraunhofer ITMP ScreeningPort, Hamburg, GermanyDepartment of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, NetherlandsInstitute of Pharmacology, Heidelberg University, Heidelberg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyWhile transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In mice, neuronal overexpression of Ppargc1a, which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity, and maximum respiratory capacity. Moreover, Ppargc1a-overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Ppargc1a aggravated neurodegeneration during experimental autoimmune encephalomyelitis, while neuronal overexpression of Ppargc1a ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.https://elifesciences.org/articles/61798multiple sclerosisEAEmitochondrianeuroprotectionPpargc1aoxidative phosphorylation |
| spellingShingle | Sina C Rosenkranz Artem A Shaposhnykov Simone Träger Jan Broder Engler Maarten E Witte Vanessa Roth Vanessa Vieira Nanne Paauw Simone Bauer Celina Schwencke-Westphal Charlotte Schubert Lukas Can Bal Benjamin Schattling Ole Pless Jack van Horssen Marc Freichel Manuel A Friese Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis eLife multiple sclerosis EAE mitochondria neuroprotection Ppargc1a oxidative phosphorylation |
| title | Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis |
| title_full | Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis |
| title_fullStr | Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis |
| title_full_unstemmed | Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis |
| title_short | Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis |
| title_sort | enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis |
| topic | multiple sclerosis EAE mitochondria neuroprotection Ppargc1a oxidative phosphorylation |
| url | https://elifesciences.org/articles/61798 |
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