Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function

Mitochondrial DNA (mtDNA) mutations cause several diseases, including mitochondrial inherited diabetes and deafness (MIDD), typically associated with the mtDNA A3243G point mutation on tRNALeu gene. The common hypothesis to explain the link between the genotype and the phenotype is that the mutation...

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Bibliographic Details
Published in:Diabetologia 2006-08, Vol.49 (8), p.1816-1826
Main Authors: DE ANDRADE, P. B. M, RUBI, B, FRIGERIO, F, VAN DEN OUWELAND, J. M. W, MAASSEN, J. A, MAECHLER, P
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Biological and medical sciences
Bone cancer
Cell Line
Cells
Diabetes
Diabetes Mellitus - genetics
Diabetes. Impaired glucose tolerance
DNA, Mitochondrial - genetics
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Genomes
Glucose
Glucose - metabolism
Glycolysis - genetics
Humans
Hypotheses
Insulin
Insulin - metabolism
Insulin Secretion
Islets of Langerhans - metabolism
Medical sciences
Metabolism
Mitochondria
Mitochondrial DNA
Mutation
Patients
Polymorphism, Single Nucleotide
Polypeptides
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Summary:Mitochondrial DNA (mtDNA) mutations cause several diseases, including mitochondrial inherited diabetes and deafness (MIDD), typically associated with the mtDNA A3243G point mutation on tRNALeu gene. The common hypothesis to explain the link between the genotype and the phenotype is that the mutation might impair mitochondrial metabolism expressly required for beta cell functions. However, this assumption has not yet been tested. We used clonal osteosarcoma cytosolic hybrid cells (namely cybrids) harbouring mitochondria derived from MIDD patients and containing either exclusively wild-type or mutated (A3243G) mtDNA. According to the importance of mitochondrial metabolism in beta cells, we studied the impact of the mutation on key parameters by comparing stimulation of these cybrids by the main insulin secretagogue glucose and the mitochondrial substrate pyruvate. Compared with control mtDNA from the same patient, the A3243G mutation markedly modified metabolic pathways leading to a high glycolytic rate (2.8-fold increase), increased lactate production (2.5-fold), and reduced glucose oxidation (-83%). We also observed impaired NADH responses (-56%), negligible mitochondrial membrane potential, and reduced, only transient ATP generation. Moreover, cybrid cells carrying patient-derived mutant mtDNA exhibited deranged cell calcium handling with increased cytosolic loads (1.4-fold higher), and elevated reactive oxygen species (2.6-fold increase) under glucose deprivation. The present study demonstrates that the mtDNA A3243G mutation impairs crucial metabolic events required for proper cell functions, such as coupling of glucose recognition to insulin secretion.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-006-0301-9