Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis.
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.
Lehman
J J
JJ
Department of Medicine, and. Department of Pathology, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Barger
P M
PM
Kovacs
A
A
Saffitz
J E
JE
Medeiros
D M
DM
Kelly
D P
DP
D000818:Animals; D000831:Animals, Newborn; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics; D019069:Cell Respiration; D002478:Cells, Cultured; D004734:Energy Metabolism; D005215:Fasting / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1