Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis
John J. Lehman, … , Denis M. Medeiros, Daniel P. Kelly
John J. Lehman, … , Denis M. Medeiros, Daniel P. Kelly
Published October 1, 2000
Citation Information: J Clin Invest. 2000;106(7):847-856. https://doi.org/10.1172/JCI10268.
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Article

Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis

Abstract

Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator–activated receptor γ coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.

Authors

John J. Lehman, Philip M. Barger, Attila Kovacs, Jeffrey E. Saffitz, Denis M. Medeiros, Daniel P. Kelly

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Forced expression of PGC-1 in cultured rat neonatal cardiac myocytes ind...
Forced expression of PGC-1 in cultured rat neonatal cardiac myocytes induces the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways. (a) The expression of mitochondrial FAO enzyme genes. The autoradiographs represent Northern (top panels) and Western (bottom panels) analyses, respectively. The panels depict the expression of the myc-tagged PGC-1 and endogenous FAO enzyme genes (MCAD and M-CPT I) in rat neonatal cardiac myocytes grown in serum-free culture conditions. Total RNA (15 μg/lane) or protein (10 μg/lane) was isolated from uninfected cells (U), or 48 hours after infection with control adenovirus expressing GFP alone (C), or an adenoviral vector expressing both GFP and PGC-1 (P). As determined by GFP fluorescence, 95–100% of the total cells plated were infected (data not shown). Adenoviral epitope-tagged PGC-1 mRNA is denoted myc-PGC-1 and endogenous PGC-1 transcripts are labeled endogenous PGC-1. The α-actin signal is shown as a control. PGC-1 protein was not detected in extracts from control adenovirus-infected cells by Western blot analysis (bottom panels), even with prolonged exposures. (b) The expression of genes and proteins involved in the TCA cycle, electron transport, and oxidative phosphorylation. The autoradiographs shown at the top represent Northern blot studies performed with total RNA isolated from cardiac myocytes under the conditions described in a. Western blot studies (bottom) were performed with cellular protein extracts prepared from myocytes 4 days after adenoviral infection. Bov. COX, bovine COX protein standards; Cyt C, cytochrome c. All data shown are representative of at least three independent experiments.