Dataset Information

Neuronal metabolic rewiring promotesresilience to neurodegeneration caused by mitochondrial dysfunction

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 mitochondria 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. Surprisingly, we identified a marked induction of pyruvate carboxylase (PCx) and other key anaplerotic enzymes involved in replenishing intermediates into the TCA cycle. Suppression of PCx aggravated 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.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Ilian Atanassov

LAB HEAD: Nils-Göran Larsson

PROVIDER: PXD019690 | Pride | 2020-08-03

REPOSITORIES: Pride

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			Action	DRS
	170511_FS1_IA_EM_214_Ctrl_0.raw	Raw
	170511_FS1_IA_EM_214_Ctrl_H.raw	Raw
	170511_FS1_IA_EM_214_Ctrl_L.raw	Raw
	170511_FS1_IA_EM_214_KO_0.raw	Raw
	170511_FS1_IA_EM_214_KO_2_0.raw	Raw

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

Motori E E Atanassov I I Kochan S M V SMV Folz-Donahue K K Sakthivelu V V Giavalisco P P Toni N N Puyal J J Larsson N-G NG

Science advances 20200828 35

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, c ...[more]

PMID: 32923630

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