PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression

Benoit R. Gauthier, Andreas Wiederkehr, Mathurin Baquié, Chunhua Dai, Alvin C. Powers, Julie Kerr-Conte, François Pattou, Raymond J. MacDonald, Jorge Ferrer, Claes B. Wollheim

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

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+/Ca2+ exchanger, restored ATP generation and GSIS in RIPDN79PDX1 islets, thereby bypassing the transcriptional defect. Thus, the genetic control by the β cell-specific factor Pdx1 of the ubiquitous gene TFAM maintains β cell mtDNA vital for ATP production and normal GSIS.

Original languageEnglish (US)
Pages (from-to)110-118
Number of pages9
JournalCell Metabolism
Volume10
Issue number2
DOIs
StatePublished - Aug 6 2009

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Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

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. (2009). PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression. Cell Metabolism, 10(2), 110-118. https://doi.org/10.1016/j.cmet.2009.07.002