Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes

Silva, José P.; Köhler, Martin; Graff, Caroline; Oldfors, Anders; Magnuson, Mark A.; Berggren, Per-Olof; Larsson, Nils-Göran

doi:10.1038/81649

Cited by 433Pancreatic function and diabetesMitochondrial Function and PathologyDiabetes and associated disorders

Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes

Silva, José P., Köhler, Martin, Graff, Caroline, Oldfors, Anders, Magnuson, Mark A., Berggren, Per-Olof, Larsson, Nils-Göran·2000·Nature Genetics

DOI 10.1038/81649

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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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TFAM deletion in pancreatic β-cells leads to diabetic mice.
“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
Mouse models with decreased mtDNA expression have increased cell death with little or no increase of oxidative stress.
“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]
β-cell specific deletion of Tfam reduces insulin secretory capacity and β-cell mass, yielding so-called mitochondrial DM.
“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]

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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: Silva, José P.
Köhler, Martin
Graff, Caroline
Oldfors, Anders
Magnuson, Mark A.
Berggren, Per-Olof
Larsson, Nils-Göran
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2000-11
Volume: 26
Issue: 3
Pages: 336-340
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/81649
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 › Surgery › 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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Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes

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