Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function
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Aims/hypothesis 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.Methods 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.Results 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.Conclusions/interpretation 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.
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Clonal cytosolic hybrid cells harboring mitochondria derived from MIDD patients exhibit impaired calcium handling and elevated ROS under metabolic stress.
“Consistent with this view, clonal cytosolic hybrid cells harboring mitochondria derived from MIDD patients exhibit impaired calcium handling and elevated ROS under metabolic stress (247, 248).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [248]
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- Authors
- de Andrade, P. B. M., Rubi, B., Frigerio, F., van den Ouweland, J. M. W., Maassen, J. A., & Maechler, P.
- Affiliations
- University of Geneva (CH)
- Leiden University Medical Center (NL)
- Corresponding author
- Maechler, P.
- Venue
- Diabetologia
- Published
- 2006-05-31
- Volume
- 49
- Issue
- 8
- Pages
- 1816-1826
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1979754659
- Cited by
- 98
- References
- 44
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 7 · 2018: 4 · 2017: 3 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondation Leenaards
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitochondrial DNA A3243G mutation, mitochondrial diabetes, beta-cell function, mitochondrial metabolism, cybrids, glycolysis, glucose oxidation, lactic acid production, mitochondrial membrane potential, ATP production, calcium handling, reactive oxygen species, insulin secretion
- MeSH terms
- Insulin Secretion, Adenosine Triphosphate, Cell Line, Diabetes Mellitus, DNA, Mitochondrial, Glucose, Glycolysis, Humans, Insulin, Islets of Langerhans, Mutation, Polymorphism, Single Nucleotide
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