Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction
| Autor: | Nicolas Toni, Elisa Motori, Vignesh Sakthivelu, Kat Folz-Donahue, Ilian Atanassov, Nils-Göran Larsson, Patrick Giavalisco, Julien Puyal, S. M. V. Kochan |
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| Rok vydání: | 2020 |
| Předmět: |
Proteomics
Programmed cell death Mitochondrial Diseases Mitochondrial disease Citric Acid Cycle Oxidative phosphorylation Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine medicine Humans Research Articles 030304 developmental biology Neurons 0303 health sciences Multidisciplinary Neurodegeneration SciAdv r-articles Cell Biology medicine.disease Mitochondria Pyruvate carboxylase Cell biology Citric acid cycle nervous system mitochondrial fusion Cellular Neuroscience 030217 neurology & neurosurgery Oxidative stress Research Article |
| Zdroj: | Sci Adv Science Advances Science advances, vol. 6, no. 35, pp. eaba8271 |
| Popis: | Proteomic analysis of dysfunctional neurons reveals a metabolic program that is activated to counteract neurodegeneration. 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. |
| Databáze: | OpenAIRE |
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