Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction.

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Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_5C5D2D246225
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction.
Journal
Science advances
Author(s)
Motori E., Atanassov I., Kochan SMV, Folz-Donahue K., Sakthivelu V., Giavalisco P., Toni N., Puyal J., Larsson N.G.
ISSN
2375-2548 (Electronic)
ISSN-L
2375-2548
Publication state
Published
Issued date
08/2020
Peer-reviewed
Oui
Volume
6
Number
35
Pages
eaba8271
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Neurodegeneration in mitochondrial disorders is considered irreversible because of limited metabolic plasticity in neurons, yet the cell-autonomous implications of mitochondrial dysfunction for neuronal metabolism in vivo are poorly understood. Here, we profiled the cell-specific proteome of Purkinje neurons undergoing progressive OXPHOS deficiency caused by disrupted mitochondrial fusion dynamics. We found that mitochondrial dysfunction triggers a profound rewiring of the proteomic landscape, culminating in the sequential activation of precise metabolic programs preceding cell death. Unexpectedly, we identified a marked induction of pyruvate carboxylase (PCx) and other anaplerotic enzymes involved in replenishing tricarboxylic acid cycle intermediates. Suppression of PCx aggravated oxidative stress and neurodegeneration, showing that anaplerosis is protective in OXPHOS-deficient neurons. Restoration of mitochondrial fusion in end-stage degenerating neurons fully reversed these metabolic hallmarks, thereby preventing cell death. Our findings identify a previously unappreciated pathway conferring resilience to mitochondrial dysfunction and show that neurodegeneration can be reversed even at advanced disease stages.
Pubmed
Web of science
Open Access
Yes
Create date
15/09/2020 13:42
Last modification date
15/01/2021 7:09
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