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Circ Res. 2014 Feb 14;114(4):626-36. doi: 10.1161/CIRCRESAHA.114.302562. Epub 2013 Dec 23.

A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth.

Author information

1
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.).

Abstract

RATIONALE:

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.

METHODS AND 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.

KEYWORDS:

Mfn1 protein, human; cardiomyopathies; mitochondrial dynamics

PMID:
24366168
PMCID:
PMC4061768
DOI:
10.1161/CIRCRESAHA.114.302562
[Indexed for MEDLINE]
Free PMC Article
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