ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation

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ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation
Title:
ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation
Journal Title:
Cell Death & Differentiation
Publication Date:
12 November 2020
Citation:
Hor, J.-H., Santosa, M. M., Lim, V. J. W., Ho, B. X., Taylor, A., Khong, Z. J., … Ng, S.-Y. (2020). ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation. Cell Death & Differentiation, 28(4), 1379–1397. doi:10.1038/s41418-020-00664-0
Abstract:
AbstractMotor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in amyotrophic lateral sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells from healthy controls, familial ALS, and sporadic ALS patients were differentiated toward spinal MNs, cortical neurons, and cardiomyocytes. Metabolic flux analyses reveal an MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, Sirtuin-3 (SIRT3) functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the National Research Foundation - NRF Fellowship
Grant Reference no. : NRF-NRFF-2018-003
Description:
ISSN:
1476-5403
1350-9047
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