The dynamic regulation of cardiac mitochondrial number and function has suggested the existence of a regulatory pathway involved in the physiologic control of mitochondrial biogenesis. Several lines of evidence presented here indicate that the transcriptional coactivator, PGC-1, is a key regulator of cardiac mitochondrial functional capacity and participates in the transduction of physiologic stimuli to energy production in the heart. First, the expression of the PGC-1 gene is upregulated after birth in the heart, before the known increase in mitochondrial biogenesis and switch from glucose to fatty acids as the chief energy substrate. Second, PGC-1 gene expression is activated by short-term fasting, a condition known to increase cardiac mitochondrial FAO rates. Third, forced expression of PGC-1 in cardiac myocytes induces mitochondrial biogenesis and coupled oxygen consumption, implicating this transcriptional coactivator in the regulation of mitochondrial respiration and, thus, ATP production in the heart.
Little is known about the mechanisms involved in the link between the broad program of mitochondrial biogenesis and the control of nuclear genes encoding enzymes of specific mitochondrial energy transduction pathways such as the FAO cycle. Recent studies indicate that PGC-1 coactivates NRF-1, a key transcriptional regulator of nuclear and mitochondrial genes encoding respiratory chain proteins (14
). Recently, we demonstrated that PGC-1 coactivates PPARα, a critical regulator of mitochondrial FAO enzyme gene expression (16
). Collectively, these results suggested that PGC-1 may serve to link the actions of NRF-1 and other master regulators of mitochondrial biogenesis to the control of specific mitochondrial pathways such as the FAO cycle. The results shown here identify PGC-1 as a component of the regulatory communication between mitochondrial biogenesis and control of FAO and TCA cycle enzyme expression. Our observation that cardiac PGC-1 gene expression is induced by fasting, a physiologic condition known to activate FAO enzyme gene expression through PPARα (23
) further supports a role for PGC-1 as a physiologically relevant coactivator of PPARα and mitochondrial fatty acid utilization in the heart. It will be of significant interest to determine whether PGC-1 coactivates other transcription factors involved in the transcriptional control of specific mitochondrial energy metabolic pathways.
The metabolic phenotype of mitochondria is cell and tissue specific. Mitochondria of the brown adipocyte are specialized for high-capacity, uncoupled respiration to generate heat. In contrast, cardiac mitochondria are efficient producers of ATP and exhibit significantly less respiratory uncoupling. Additionally, the contribution of specific mitochondrial energy metabolic pathways to the production of reducing equivalents for generation of ATP through oxidative phosphorylation varies among tissue types. For example, in contrast to the heart, which has a high capacity for the oxidation of fats, mitochondrial ATP production in the brain relies primarily on reducing equivalents generated by glucose oxidation. Consistent with the tissue-specific mitochondrial energy-substrate preferences, expression of FAO enzymes is markedly higher in heart mitochondria compared with that of the brain (18
). We propose that PGC-1 plays a role in determining the metabolic phenotype of mitochondria among specialized cell types. It is possible that the availability of PGC-1 partners in a given tissue, such as NRF-1, PPARα, PPARγ, and other, as yet unidentified, transcription factors dictate the level of expression of enzymes and proteins in specific mitochondrial pathways. This notion is supported by the observation that PGC-1 is capable of inducing either uncoupled (15
) or coupled (shown here) respiration in a cell type–specific manner and the finding that prolonged cold exposure induces PGC-1 gene expression in brown adipose tissue and in skeletal muscle, but not in the heart (14
). Taken together, these findings suggest that PGC-1 controls mitochondrial functional capacity in a tissue-specific manner.
Our data indicate that PGC-1 is capable of promoting biogenesis of mitochondria that support primarily coupled respiration in neonatal cardiac myocytes in culture. However, these results do not allow us to conclude that PGC-1 induces coupled respiration in the adult heart in vivo under all circumstances. It is possible that PGC-1 induces coupled or uncoupled mitochondrial respiration in vivo in the heart in different physiologic contexts. Unfortunately, given the cardiac dysfunction of the MHC-PGC-1 mice, functional studies of mitochondria from the transgenic mice would be difficult to interpret because of secondary effects related to heart failure. Future studies using inducible transgenic expression systems should allow the evaluation of the primary effects of PGC-1 on mitochondrial function in vivo.
Evidence is emerging that alterations in mitochondrial functional capacity are involved in the pathogenesis of a wide variety of inherited and acquired human diseases, many of which cause cardiomyopathy and heart failure (1
). Inborn errors in mitochondrial FAO enzymes and mutations of the mitochondrial genome are now recognized as important causes of cardiomyopathy, metabolic disturbances, and skeletal myopathy in pediatric and adult populations. Interestingly, the clinical manifestations of mitochondrial diseases is often precipitated by environmental or physiologic “stressors” that increase the demand for cardiac or skeletal muscle mitochondrial energy production, such as exercise or fasting, suggesting that a mismatch between energy demand and supply precipitates organ dysfunction (1
). Common acquired cardiac diseases are also associated with mitochondrial functional abnormalities. Cardiac hypertrophy due to pressure overload, such as that which occurs with hypertension, results in a downregulation of FAO enzyme expression and reduced capacity for mitochondrial oxidation of fats (22
). Mitochondrial DNA deletions also occur with aging and in the ischemic heart (4
). Future studies aimed at delineating the activity of PGC-1 in cardiac disease states associated with mitochondrial dysfunction may help define the potential role of this coactivator in the pathogenesis of specific cardiac diseases. Considering the wide range of pathophysiologic states in which cardiac mitochondrial functional capacity is altered, the PGC-1 regulatory pathway is a candidate target for the investigation of novel experimental and possibly therapeutic strategies aimed at the amelioration of energy metabolic dysfunction in a variety of cardiac diseases.