PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression.
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.
Gauthier
Benoit R
BR
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. benoit.gauthier@cabimer.es
Wiederkehr
Andreas
A
Baquié
Mathurin
M
Dai
Chunhua
C
Powers
Alvin C
AC
Kerr-Conte
Julie
J
Pattou
François
F
MacDonald
Raymond J
RJ
Ferrer
Jorge
J
Wollheim
Claes B
CB
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D024101:Mitochondrial Proteins; D019831:Sodium-Calcium Exchanger; C499631:TFAM protein, human; C081930:Tfam protein, mouse; C489030:Tfam protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose; D004318:Doxycycline