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CRISPR-Mediated Induction of Neuron-Enriched Mitochondrial Proteins Boosts Direct Glia-to-Neuron Conversion

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 neu...

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Detalles Bibliográficos
Autores principales: Russo, Gianluca L., Sonsalla, Giovanna, Natarajan, Poornemaa, Breunig, Christopher T., Bulli, Giorgia, Merl-Pham, Juliane, Schmitt, Sabine, Giehrl-Schwab, Jessica, Giesert, Florian, Jastroch, Martin, Zischka, Hans, Wurst, Wolfgang, Stricker, Stefan H., Hauck, Stefanie M., Masserdotti, Giacomo, Götz, Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939544/
https://www.ncbi.nlm.nih.gov/pubmed/33202244
http://dx.doi.org/10.1016/j.stem.2020.10.015
Descripción
Sumario: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.