Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia

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.