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.
Article and author information
Author details
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.
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).
Reviewing Editor
- Brandon K Harvey, NIDA/NIH, United States
Publication history
- Received: August 5, 2020
- Accepted: February 10, 2021
- Accepted Manuscript published: February 10, 2021 (version 1)
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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