The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes
Abstract
Mitochondrial dysfunction is an important contributor to human pathology and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of beta-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca(2+)-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant beta-cells initially display reduced stimulus-secretion coupling, later followed by beta-cell loss. This animal model reproduces the beta-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.
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In the citing paper
“TFAM deletion in pancreatic β-cells leads to diabetic mice (Silva et al., 2000).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Silva et al., 2000
In the citing paper
“We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”
From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [15]
In the citing paper
“Consistent with this possibility, -cell specific deletion of Tfam reduces insulin secretory capacity and -cell mass, yielding so-called mitochondrial DM (241).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [241]
Citations
Cites
Mitochondrial diseases in man and mouse
Wallace, D. C. (1999) · Science · doi:10.1126/science.283.5407.1482 · Cited by 3,060
Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas
Lacy, P. E., & Kostianovsky, M. (1967) · Diabetes · doi:10.2337/diab.16.1.35 · Cited by 2,741
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., & Clayton, D. A. (1998) · Nature Genetics · doi:10.1038/ng0398-231 · Cited by 1,594
Postic, C., Shiota, M., Niswender, K. D., Jetton, T. L., Chen, Y., Moates, J. M., Shelton, K. D., Lindner, J., Cherrington, A. D., & Magnuson, M. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.1.305 · Cited by 1,302
Kulkarni, R., Brüning, J. C., Winnay, J. N., Postic, C., Magnuson, M. A., & Kahn, C. R. (1999) · Cell · doi:10.1016/s0092-8674(00)80546-2 · Cited by 1,148
A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.
Kadowaki, T., Kadowaki, H., Mori, Y., Tobe, K., Sakuta, R., Suzuki, Y., Tanabe, Y., Sakura, H., Awata, T., Goto, Y.-I., et al. (1994) · New England Journal of Medicine · doi:10.1056/nejm199404073301403 · Cited by 551
Similarity of Human Mitochondrial Transcription Factor 1 to High Mobility Group Proteins
Parisi, M. A., & Clayton, D. A. (1991) · Science · doi:10.1126/science.2035027 · Cited by 548
MOLECULAR GENETIC ASPECTS OF HUMAN MITOCHONDRIAL DISORDERS
Larsson, N.-G., & Clayton, D. A. (1995) · Annual Review of Genetics · doi:10.1146/annurev.ge.29.120195.001055 · Cited by 493
Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., et al. (1999) · Nature Genetics · doi:10.1038/5089 · Cited by 435
Self-citationMajamaa, K., Moilanen, J. S., Uimonen, S., Remes, A. M., Salmela, P. I., Kärppä, M., Majamaa‐Voltti, K., Rusanen, H., Sorri, M., PEUHKURINEN, K. J., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/301959 · Cited by 385
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Wallace, D. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095751 · Cited by 3,185
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734
Self-citationRole of Oxidative Modifications in Atherosclerosis
Stocker, R., & Keaney, J. F. (2004) · Physiological Reviews · doi:10.1152/physrev.00047.2003 · Cited by 2,651
Mitochondrial DNA mutations in human disease
Taylor, R. W., & Turnbull, D. M. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1606 · Cited by 1,922
Mitochondria: Dynamic Organelles in Disease, Aging, and Development
Chan, D. C. (2006) · Cell · doi:10.1016/j.cell.2006.06.010 · Cited by 1,987
Metadata
- Authors
- Silva, J. P., Köhler, M., Graff, C., Oldfors, A., Magnuson, M. A., Berggren, P.-O., & Larsson, N.-G.
- Affiliations
- Karolinska University Hospital (SE)
- Sahlgrenska University Hospital (SE)
- Vanderbilt University (US)
- Corresponding author
- Larsson, Nils-Göran
- ORCID
- Venue
- Nature Genetics
- Published
- 2000-11
- Volume
- 26
- Issue
- 3
- Pages
- 336-340
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1579112009
- Cited by
- 433
- References
- 21
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 11 · 2023: 12 · 2022: 20 · 2021: 12 · 2020: 15 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 14 · 2015: 13 · 2014: 17 · 2013: 16 · 2012: 19
- FWCI
- 19.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- mitochondrial diabetes, mitochondrial dysfunction, TFAM, beta cell destruction, insulin secretion, stimulus-secretion coupling, mtDNA depletion, oxidative phosphorylation, mitochondrial membrane potential, calcium signaling, beta-cell mass, electron transport chain, pancreatic islets, mouse model
- MeSH terms
- Insulin Secretion, Adenosine Triphosphate, Age Factors, Animals, Calcium, Electron Transport Complex IV, Diabetes Mellitus, Disease Models, Animal, DNA-Binding Proteins, DNA, Mitochondrial, Exocytosis, Glucose, High Mobility Group Proteins, Humans, Insulin, Islets of Langerhans, Mice, Transgenic, Nuclear Proteins, Organ Specificity, Oxidative Phosphorylation, Recombinant Fusion Proteins, Secretory Rate, Succinate Dehydrogenase, Transcription Factors, Transcription, Genetic, Viral Proteins, Potassium Channels, Trans-Activators, Ion Transport, Gene Targeting, Disease Progression, Transgenes, Integrases, Calcium Channels, L-Type, Mitochondrial Proteins, Xenopus Proteins, Mice
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