Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa).
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.
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore.
Benjamin L
BL
Farah
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore.
Rohit A
RA
Sinha
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Yajun
Y
Wu
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore.
Brijesh K
BK
Singh
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore.
Andrea
A
Lim
Faculty of Medicine, Tohoku University, Sendai, Japan.
Masahiro
M
Hirayama
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
Dustin J
DJ
Landau
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Boon Huat
BH
Bay
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.|Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Dwight D
DD
Koeberl
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore.|Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Paul M
PM
Yen
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002952:Citric Acid Cycle / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008112:Liver Glycogen / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D010085:Oxidative Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D008112:Liver Glycogen; D034741:RNA, Small Interfering; D014280:Triglycerides; D005952:Glucose-6-Phosphatase