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

Russo, Gianluca Luigi; Sonsalla, Giovanna; Natarajan, Poornemaa; Breunig, Christopher T.; Mascagni, Giulia; 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

doi:10.1016/j.stem.2020.11.017

Cited by 15 publications

(13 citation statements)

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“…It is increasingly recognised that direct reprogramming imposes significant cellular stress (Babos et al, 2019;Russo et al, 2021;Zhou et al, 2019). Neurons have very different metabolic needs from astrocytes.…”

Section: Herreromentioning

confidence: 99%

Reprogramming cellular identity in vivo

2022

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Cellular identity is established through complex layers of genetic regulation, forged over a developmental lifetime. An expanding molecular toolbox is allowing us to manipulate these gene regulatory networks in specific cell types in vivo. In principle, if we found the right molecular tricks, we could rewrite cell identity and harness the rich repertoire of possible cellular functions and attributes. Recent work suggests that this rewriting of cell identity is not only possible, but that newly induced cells can mitigate disease phenotypes in animal models of major human diseases. So, is the sky the limit, or do we need to keep our feet on the ground? This Spotlight synthesises key concepts emerging from recent efforts to reprogramme cellular identity in vivo. We provide our perspectives on recent controversies in the field of glia-to-neuron reprogramming and identify important gaps in our understanding that present barriers to progress.

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Section: Herreromentioning

confidence: 99%

Reprogramming cellular identity in vivo

2022

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“…Lactate in the RPE can be converted to pyruvate, via lactate dehydrogenase, which is then able to enter the mitochondrial matrix and completely oxidized to power ATP production via oxidative phosphorylation. Interestingly, this complementary metabolic relationship between photoreceptor and RPE cells is similar to that J o u r n a l P r e -p r o o f between neurons and glial cells, which rely on lactate and glucose as fuel sources, respectively (13,14).…”

Section: Introductionmentioning

confidence: 77%

Vitamin B3, nicotinamide, enhances mitochondrial metabolism to promote differentiation of the retinal pigment epithelium

Hazim¹,

Paniagua²,

Tang³

et al. 2022

Journal of Biological Chemistry

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“…Instead, Bcl2 reduces neuronal reprogramming-associated lipid peroxidation, the blockage of which prevents induced neurons from undergoing ferroptosis. Additionally, a proteomic study revealed striking differences in mitochondrial proteins in neurons versus astrocytes, and the specific expression of neuronal genes improved neuronal reprogramming efficacy ( Russo et al, 2021 ). Given the central role of metabolism, the potential impact of diet and dietary supplements on Müller glia regenerative response has, to the best of our knowledge, not been reported.…”

Section: Endogenous Retinal Regeneration: Targeting the Latent Repair...mentioning

confidence: 99%

Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

Hanna

David

Touahri

et al. 2022

Front. Cell Dev. Biol.

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Vision commences in the retina with rod and cone photoreceptors that detect and convert light to electrical signals. The irreversible loss of photoreceptors due to neurodegenerative disease leads to visual impairment and blindness. Interventions now in development include transplanting photoreceptors, committed photoreceptor precursors, or retinal pigment epithelial (RPE) cells, with the latter protecting photoreceptors from dying. However, introducing exogenous human cells in a clinical setting faces both regulatory and supply chain hurdles. Recent work has shown that abnormalities in central cell metabolism pathways are an underlying feature of most neurodegenerative disorders, including those in the retina. Reversal of key metabolic alterations to drive retinal repair thus represents a novel strategy to treat vision loss based on cell regeneration. Here, we review the connection between photoreceptor degeneration and alterations in cell metabolism, along with new insights into how metabolic reprogramming drives both retinal development and repair following damage. The potential impact of metabolic reprogramming on retinal regeneration is also discussed, specifically in the context of how metabolic switches drive both retinal development and the activation of retinal glial cells known as Müller glia. Müller glia display latent regenerative properties in teleost fish, however, their capacity to regenerate new photoreceptors has been lost in mammals. Thus, re-activating the regenerative properties of Müller glia in mammals represents an exciting new area that integrates research into developmental cues, central metabolism, disease mechanisms, and glial cell biology. In addition, we discuss this work in relation to the latest insights gleaned from other tissues (brain, muscle) and regenerative species (zebrafish).

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

Cited by 15 publications

References 0 publications

Reprogramming cellular identity in vivo

Reprogramming cellular identity in vivo

Vitamin B3, nicotinamide, enhances mitochondrial metabolism to promote differentiation of the retinal pigment epithelium

Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

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