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

作者：John J. Lehman, Philip M. Barger, Attila Kovács, Jeffrey E. Saffitz, Denis M. Medeiros, Daniel P. Kelly · 发表于：Journal of Clinical Investigation · 年份：2000 · DOI：10.1172/jci10268 · 被引用次数：1285 · 研究领域：Adipose Tissue and Metabolism、Mitochondrial Function and Pathology、Peroxisome Proliferator-Activated Receptors

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 gamma 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.