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Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination

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Abstract

The metabolic needs of the premature/premyelinating oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation from the pre-OLs to the OLs is not fully understood. Here, we show that the terminal maturation and higher mitochondrial respiration in the OLs is an integrated process controlled through pyruvate dehydrogenase complex (Pdh). Combined bioenergetics and metabolic studies show that OLs show elevated mitochondrial respiration than the pre-OLs. Our signaling studies show that the increased mitochondrial respiration activity in the OLs is mediated by the activation of Pdh due to inhibition of the pyruvate dehydrogenase kinase-1 (Pdhk1) that phosphorylates and inhibits Pdh activity. Accordingly, when Pdhk1 is directly expressed in the pre-OLs, they fail to mature into the OLs. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh-dependent acetyl-CoA generation from pyruvate contributes to the acetylation of the bHLH family transcription factor, oligodendrocyte transcription factor 1 (Olig1) which is known to be involved in the OL maturation. Pdh inhibition via direct expression of Pdhk1 in the pre-OLs blocks the Olig1-acetylation and OL maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is however reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status in the cuprizone model. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications in the development of therapies for a variety of demyelinating disorders including multiple sclerosis.

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Data availability

All the data sets generated are not publically available do to the originality of the work and being submitted first time for the publication. However, these data are retained and will be made available after a reasonable request is made to the corresponding authors.

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Acknowledgements

The authors would like to thank confocal laser scanning facility at the Department of Neurosurgery, Henry Ford Health (HFH). We would also like to thank Polyplus™ for sharing transfection reagents with us as a generous gift.

Funding

This work is in-part supported by research grants from the National Multiple Sclerosis Society (US) (RG-2111–38733), the US National Institutes of Health (NS112727 and AI144004) and Henry Ford Hospital Internal support (A10270 and A30967) to SG. The funders had no role in the study design, data collection, and interpretation, or the decision to submit the work for publication.

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  1. Department of Neurology, Henry Ford Health, Detroit, MI, 48202, USA

    M. Sajad, Insha Zahoor, Faraz Rashid, Mirela Cerghet & Shailendra Giri

  2. Gynecologic Oncology and Developmental Therapeutics Research Program, Henry Ford Health Hospital, Detroit, MI, 48202, USA

    Ramandeep Rattan

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Contributions

M. Sajad, Faraz Rashid, and Insha Zahoor collected the data; M. Sajad, Insha Zahoor, and Faraz Rashid analyzed the data. Ramandeep Rattan helped in the analysis of metabolic seahorse data. M. Sajad wrote the manuscript, and Shailendra Giri edited the manuscript. All the authors have approved the final data and the final version of the manuscript.

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Sajad, M., Zahoor, I., Rashid, F. et al. Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination. Mol Neurobiol 61, 397–410 (2024). https://doi.org/10.1007/s12035-023-03546-x

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