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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PGC-1 promotes mitochondrial biogenesis in cardiac myocytes. (a) Fluores...
PGC-1 promotes mitochondrial biogenesis in cardiac myocytes. (a) Fluorescence micrograph panels representing the use of the mitochondrion-selective dye MitoTracker to estimate mitochondrial capacity in cardiac myocytes 5 days after infection with either a GFP-expressing control adenovirus (Ad-GFP) or an adenovirus expressing both GFP and PGC-1 (Ad-PGC-1). MitoTracker, which is oxidized, sequestered, and conjugated in mitochondria, is identified by the orange-red color. GFP, which confirms adenoviral infection, is seen as a nuclear-localized green color. (b) Electron micrographs obtained from sections of cultured rat neonatal cardiac myocyte pellets representing cells infected with either Ad-GFP (Control) or Ad-PGC-1 (PGC-1). The far right panel is representative of regions containing markedly enlarged mitochondria observed in the PGC-1–expressing myocytes. Bar represents 1 μm, the size standard for all three panels. M, mitochondria; N, nucleus.