ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation
Open Access
- 12 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 28 (4), 1379-1397
- https://doi.org/10.1038/s41418-020-00664-0
Abstract
Motor 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.Keywords
Funding Information
- National Research Foundation Singapore (NRF-NRFF-2018-003)
- A*STAR | Institute of Molecular and Cell Biology
This publication has 37 references indexed in Scilit:
- Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesisProceedings of the National Academy of Sciences of the United States of America, 2013
- The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseasesNeurobiology of Disease, 2013
- Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditionsNature Protocols, 2012
- A functionally characterized test set of human induced pluripotent stem cellsNature Biotechnology, 2011
- Energy metabolism in amyotrophic lateral sclerosisThe Lancet Neurology, 2011
- Edaravone, a free radical scavenger, protects components of the neurovascular unit against oxidative stress in vitroBrain Research, 2010
- A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasisProceedings of the National Academy of Sciences of the United States of America, 2008
- Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine AcetylationMolecular and Cellular Biology, 2007
- Riluzole and amyotrophic lateral sclerosis survival: a population‐based study in southern ItalyEuropean Journal of Neurology, 2007
- Mutated Human SOD1 Causes Dysfunction of Oxidative Phosphorylation in Mitochondria of Transgenic MiceOnline Journal of Public Health Informatics, 2002