Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 997–1006 | Cite as

Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia

  • Jun-Ho Cho
  • Goo-Young Kim
  • Brian C. Mansfield
  • Janice Y. ChouEmail author
Glycogen Storage Disease


Glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unclear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD+-dependent deacetylase that can deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-α-deficient livers impairs PGC-1α activity, leading to mitochondrial dysfunction. Here we show that the G6Pase-α-deficient livers display defective PGC-1α signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC-1α activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase-α expression normalized SIRT1 signaling. We now show that restoration of hepatic G6Pase-α expression also restores PGC-1α activity and mitochondrial function. Finally, we show that HCA/HCC lesions found in G6Pase-α-deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1/PGC-1α signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA/HCC development in GSD-Ia.


Mitochondria Glucose-6-phosphatase-α SIRT1/ PGC-1α signaling Liver homeostasis 



Glycogen storage disease type Ia




Hepatocellular adenoma


Hepatocellular carcinoma


Sirtuin 1


Peroxisome proliferator-activated receptor-γ coactivator 1α




Oxidative phosphorylation


Electron transport chain


General control non-repressed protein 5


Weeks post G6pc gene deletion


Recombinant adeno-associated virus


Mitochondrially encoded cytochrome c oxidase 1


Mitochondrial gene encoded subunit 6 of mitochondrial ATP synthase


Mitochondrial transcription factor A


ATP-citrate lyase


PTEN-induced putative kinase 1





We thank Dr. Pierre Chambon for the gift of the AlbCreERT2 mice. Microscopy imaging was performed at the Microscopy & Imaging Core (National Institute of Child Health and Human Development, NIH) with the assistance of Chip Dye.


This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; and by the Children’s Fund for Glycogen Storage Disease Research.

Compliance with ethical standards

Conflict of interest

J.-H. Cho, G.-Y. Kim, B. C. Mansfield, and J. Y. Chou declare that they have no conflict of interest.

Animal rights

All institutional and national guidelines for the care and use of laboratory animals were followed.


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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  1. 1.Section on Cellular Differentiation, Division of Translational MedicineEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthBethesdaUSA
  2. 2.Foundation Fighting BlindnessColumbiaUSA

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