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PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression
Open accessAbstract
Mutations in the transcription factor Pdx1 cause maturity-onset diabetes of the young 4 (MODY4). Islet transduction with dominant-negative Pdx1 (RIPDN79PDX1) impairs mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). Transcript profiling revealed suppression of nuclear-encoded mitochondrial factor A (TFAM). Herein, we show that Pdx1 suppression in adult mice reduces islet TFAM expression coinciding with hyperglycemia. We define TFAM as a direct target of Pdx1 both in rat INS1 cells and human islets. Adenoviral overexpression of TFAM along with RIPDN79PDX1 in isolated rat islets rescued mitochondrial DNA (mtDNA) copy number and restored respiratory chain activity as well as glucose-induced ATP synthesis and insulin secretion. CGP37157, which blocks the mitochondrial Na(+)/Ca(2+) exchanger, restored ATP generation and GSIS in RIPDN79PDX1 islets, thereby bypassing the transcriptional defect. Thus, the genetic control by the beta cell-specific factor Pdx1 of the ubiquitous gene TFAM maintains beta cell mtDNA vital for ATP production and normal GSIS.
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“TFAM overexpression in rat pancreatic islet cells normalized Nd1 mRNA levels and restored glucose-induced ATP generation along with insulin secretion (Gauthier et al., 2009).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Gauthier et al., 2009
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“Moreover, Tfam has recently been shown to be directly downstream of PDX1, a key transcription factor for -cell development (242).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [242]
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Metadata
- Authors
- Gauthier, B. R., Wiederkehr, A., Baquié, M., Dai, C., Powers, A. C., Kerr-Conte, J., Pattou, F., MacDonald, R. J., Ferrer, J., & Wollheim, C. B.
- Affiliations
- University of Geneva (CH)
- Vanderbilt University (US)
- Inserm (FR)
- The University of Texas Southwestern Medical Center (US)
- Hospital Clínic de Barcelona (ES)
- Corresponding author
- Gauthier, Benoit R.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 10
- Issue
- 2
- Pages
- 110-118
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4012862
- OpenAlex
- W2061113221
- Cited by
- 115
- References
- 41
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 5 · 2022: 10 · 2021: 4 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 7 · 2013: 2 · 2012: 10
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1446 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (DK20593, DK68854, DK69603)
- Juvenile Diabetes Research Foundation International
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310000-116750/1, 310030-119763, 32-66907.01, LSHM-CT-2006-518153)
- 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
- PDX1, TFAM, mitochondrial dysfunction, insulin secretion, glucose-stimulated insulin secretion, pancreatic beta cells, mitochondrial DNA copy number, electron transport chain, ATP production, mitochondrial Na+/Ca2+ exchanger, hyperglycemia, islets
- MeSH terms
- Insulin Secretion, Animals, Base Sequence, DNA-Binding Proteins, Doxycycline, Glucose, High Mobility Group Proteins, Humans, Insulin, Islets of Langerhans, Male, Mice, Transgenic, Mitochondria, Promoter Regions, Genetic, Transcription Factors, Trans-Activators, Rats, Wistar, Homeodomain Proteins, Sodium-Calcium Exchanger, Mitochondrial Proteins, Mice, Rats
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