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CRISPR-mediated induction of neuron-enriched mitochondrial proteins boosts direct glia-to-neuron conversion.

Cell Stem Cell 28, 524-534.e7 (2021)
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Open Access Gold (Paid Option)
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Astrocyte-to-neuron conversion is a promising avenue for neuronal replacement therapy. Neurons are particularly dependent on mitochondrial function, but how well mitochondria adapt to the new fate is unknown. Here, we determined the comprehensive mitochondrial proteome of cortical astrocytes and neurons, identifying about 150 significantly enriched mitochondrial proteins for each cell type, including transporters, metabolic enzymes, and cell-type-specific antioxidants. Monitoring their transition during reprogramming revealed late and only partial adaptation to the neuronal identity. Early dCas9-mediated activation of genes encoding mitochondrial proteins significantly improved conversion efficiency, particularly for neuron-enriched but not astrocyte-enriched antioxidant proteins. For example, Sod1 not only improves the survival of the converted neurons but also elicits a faster conversion pace, indicating that mitochondrial proteins act as enablers and drivers in this process. Transcriptional engineering of mitochondrial proteins with other functions improved reprogramming as well, demonstrating a broader role of mitochondrial proteins during fate conversion.

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Publication type Article: Journal article
Document type Scientific Article
Keywords CRISPR-a; antioxidant; direct reprogramming; metabolism; mitochondria; proteome; Glutamate Carrier Slc25a22; Cell Identity; Stem; Identification; Proteome; Encephalopathy; Metabolism; Mechanisms; Astrocytes; Mutation
ISSN (print) / ISBN 1934-5909
e-ISSN 1875-9777
Journal Cell Stem Cell
Quellenangaben Volume: 28, Issue: 3, Pages: 524-534.e7 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Grants SPP2127
AMPro Project (Aging and Metabolic Programming) network funds of the Helmholtz Association
SyNergy-HMGU
ERAnet
advanced ERC ChroNeuroRepair
German Research Foundation
Fondation Rodger de Spoelberch