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

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

Research output: Contribution to journalArticle

883 Scopus citations

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.

Original languageEnglish
Pages (from-to)847-856
Number of pages10
JournalJournal of Clinical Investigation
Volume106
Issue number7
DOIs
StatePublished - Oct 2000

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