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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...

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Main Authors: Rosenkranz, Sina Cathérine (Author) , Shaposhnykov, Artem A (Author) , Träger, Simone (Author) , Engler, Jan Broder (Author) , Witte, Maarten E (Author) , Roth, Vanessa (Author) , Vieira, Vanessa (Author) , Paauw, Nanne (Author) , Bauer, Simone (Author) , Schwencke-Westphal, Celina (Author) , Schubert, Charlotte (Author) , Bal, Lukas Can (Author) , Schattling, Benjamin (Author) , Pless, Ole (Author) , van Horssen, Jack (Author) , Freichel, Marc (Author) , Friese, Manuel A (Author)
Format: Article (Journal)
Language:English
Published: 10 February 2021
In: eLife
Year: 2021, Volume: 10, Pages: 1-26
ISSN:2050-084X
DOI:10.7554/eLife.61798
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.7554/eLife.61798
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 26.06.2021
Physical Description:Online Resource
ISSN:2050-084X
DOI:10.7554/eLife.61798

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