Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction.
- Motori E Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
- Atanassov I Proteomics Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
- Kochan SMV Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany.
- Folz-Donahue K FACS & Imaging Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
- Sakthivelu V Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany.
- Giavalisco P Metabolomics Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
- Toni N Center for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University Hospital, Lausanne University, Lausanne, Switzerland.
- Puyal J Department of Fundamental Neurosciences, University of Lausanne, 1005 Lausanne, Switzerland.
- Larsson NG Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
- 2020-09-14
Published in:
- Science advances. - 2020
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1126/sciadv.aba8271
- PMID 32923630
- Persistent URL
- https://sonar.ch/global/documents/1598
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