Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)

Benjamin L Farah,Brijesh K Singh,Boon Huat Bay,Dustin J Landau,Masahiro Hirayama,Paul M Yen,Yajun Wu,Rohit A Sinha,Dwight D Koeberl,Andrea Lim

doi:10.1038/srep44408

Abstract

Glycogen storage disease type Ia (GSDIa, von Gierke disease) is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, an enzyme which catalyses the final step of gluconeogenesis and glycogenolysis. Clinically, GSDIa is characterized by fasting hypoglycaemia and hepatic glycogen and triglyceride overaccumulation. The latter leads to steatohepatitis, cirrhosis, and the formation of hepatic adenomas and carcinomas. Currently, little is known about the function of various organelles and their impact on metabolism in GSDIa. Accordingly, we investigated mitochondrial function in cell culture and mouse models of GSDIa. We found impairments in oxidative phosphorylation and changes in TCA cycle metabolites, as well as decreased mitochondrial membrane potential and deranged mitochondrial ultra-structure in these model systems. Mitochondrial content also was decreased, likely secondary to decreased mitochondrial biogenesis. These deleterious effects culminated in the activation of the mitochondrial apoptosis pathway. Taken together, our results demonstrate a role for mitochondrial dysfunction in the pathogenesis of GSDIa, and identify a new potential target for the treatment of this disease. They also provide new insight into the role of carbohydrate overload on mitochondrial function in other hepatic diseases, such as non-alcoholic fatty liver disease.

Highlights

The metabolic derangements seen in GSDIa previously were thought to be due solely to the increased levels of various metabolites such as glucose-6-phosphate and acetyl-CoA “pushing” biochemical pathways towards glycogen, nucleotide, and lipid synthesis
Analysing both cell culture and mouse models of GSDIa, we found that oxidative metabolism was impaired in this disease, and was associated with changes in the levels of tri-carboxylic acid cycle (TCA cycle) intermediates, derangements in mitochondrial structure, and a decrease in mitochondrial number
Since oxidative metabolism is an important function of mitochondria, we evaluated the function of the electron transport chain by performing oximetry on G6PC KD AML-12 cells using a Seahorse XF24 mitochondrial flux analyser, 96 hours after knock-down

Summary

Introduction

The metabolic derangements seen in GSDIa previously were thought to be due solely to the increased levels of various metabolites such as glucose-6-phosphate and acetyl-CoA “pushing” biochemical pathways towards glycogen, nucleotide, and lipid synthesis. We hypothesized that mitochondrial dysfunction may play a role in the increased apoptosis observed in this disorder[15]. Analysing both cell culture and mouse models of GSDIa, we found that oxidative metabolism was impaired in this disease, and was associated with changes in the levels of tri-carboxylic acid cycle (TCA cycle) intermediates, derangements in mitochondrial structure, and a decrease in mitochondrial number. These changes culminate in an activation of the mitochondrial apoptosis cascade. Our findings shed new light on the role of mitochondrial dysfunction in the pathogenesis of GSDIa and carbohydrate excess, and suggest new potential molecular targets for their treatment

Methods

Results

Conclusion