title: A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth.
abstract: BACKGROUND
  Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood.
  
  
  OBJECTIVE
  Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice.
  
  
  RESULTS
  Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (Mfn1, Opa1) and fission (Drp1, Fis1) was altered in the hearts of PGC-1α/β-deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α on a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart.
  
  
  CONCLUSIONS
  These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics.
authors.affiliation: From the Diabetes and Obesity Research Center, Cardiovascular Pathobiology Program, Sanford-Burnham Medical Research Institute, Orlando, FL (O.J.M., L.L., M.M.S., T.C.L., D.P.K.); Institute for Research in Biomedicine, Barcelona, Spain (A.Z.); Department de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain (A.Z.); CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain (A.Z.); Department of Biochemistry, University of Wisconsin-Madison, WI (M.P.K., A.D.A.); and Departments of Medicine, Pharmacology, and Cancer Biology, Duke University, Durham, NC (D.M.M.).
authors.forename: Ola J
authors.initials: OJ
authors.lastname: Martin
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.forename: Mangala M
authors.initials: MM
authors.lastname: Soundarapandian
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000367:Age Factors; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004734:Energy Metabolism / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C498809:Opa1 protein, mouse
keywords: Mfn1 protein, human; cardiomyopathies; mitochondrial dynamics