Universität zu Köln

Motori, E., Atanassov, I, Kochan, S. M., V, Folz-Donahue, K., Sakthivelu, V, Giavalisco, P., Toni, N., Puyal, J. and Larsson, N-G (2020). Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction. Sci. Adv., 6 (35). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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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 mitochondria! dysfunction and show that neurodegeneration can be reversed even at advanced disease stages.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Motori, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Atanassov, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Kochan, S. M., V UNSPECIFIED UNSPECIFIED UNSPECIFIED Folz-Donahue, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sakthivelu, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Giavalisco, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toni, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Puyal, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Larsson, N-G UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-324205
DOI:	10.1126/sciadv.aba8271
Journal or Publication Title:	Sci. Adv.
Volume:	6
Number:	35
Date:	2020
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	2375-2548
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHROMATOGRAPHY-MASS SPECTROMETRY; BENZOYL CHLORIDE DERIVATIZATION; CHAIN AMINO-ACIDS; MALIC ENZYME; PYRUVATE CARBOXYLATION; GLUTAMINE-METABOLISM; PRIMARY CULTURES; EXPRESSION; BRAIN; MUTATIONS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32420