Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis
- University Medical Centre Hamburg-Eppendorf, Germany
- University Medical Centre Hamburg-Eppendorf Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Germany
- Amsterdam UMC, Netherlands
- Fraunhofer IME, Germany
- University of Heidelberg, Germany
Abstract
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 posttranslational inactivation of the transcriptional co-regulator 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 (EAE), 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.
Data availability
All current data have been provided. Supplemental figures are included in the article file. All individual data are reported within the figure graphs as scatter plots. Numerical data for Figure 3E, 5A and 5C can be found as Source Data.Enrichment analysis was performed using the function 'gseGO' of the R package clusterProfiler; plotting was performed with the R packages ggplot2, clusterProfiler and tidyheatmap.Normalization, calcium spikes, base line detection, and analysis of the calcium clearance rate were performed with the custom-made script written on Python 3.6 (https://github.com/scriptcalcium/PGC1alpha).
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Bassoon proteinopathy drives neurodegeneration in multiple sclerosisGene Expression Omnibus: Accession number GSE104899.
Article and author information
Author details
Benjamin Schattling
Funding
Stifterverband (Clinician-Scientist Fellowship)
- Sina C Rosenkranz
Gemeinnützige Hertie-Stiftung (Hertie Network of Excellence in Clinical Neuroscience)
- Sina C Rosenkranz
Deutsche Forschungsgemeinschaft (FR1720/9-1,FR1720/9-2)
- Manuel A Friese
Deutsche Forschungsgemeinschaft (FR1638/3-1,FR1638/3-2)
- Marc Freichel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Brandon K Harvey, NIDA/NIH, United States
Ethics
Animal experimentation: All animal care and experimental procedures were performed according to institutional guidelines and conformed to requirements of the German Animal Welfare Act. All animal experiments were approved by the local ethics committee (Behörde für Soziales, Familie, Gesundheit und Verbraucherschutz in Hamburg; G22/13 and 122/17). We conducted all procedures in accordance with the ARRIVE guidelines (Kilkenny et al., 2010).
Version history
- Received: August 5, 2020
- Accepted: February 10, 2021
- Accepted Manuscript published: February 10, 2021 (version 1)
- Version of Record published: March 25, 2021 (version 2)
- Version of Record updated: February 2, 2022 (version 3)
Copyright
© 2021, Rosenkranz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis
eLife 10:e61798.
https://doi.org/10.7554/eLife.61798
