Abstract 13487: A Key Role for the PGC-1 Transcriptional Coactivators in Cardiac Postnatal Mitochondrial Maturation and Dynamics
The adult heart is equipped with a high capacity mitochondrial system to meet the energy demands of a constant pump. Recently, we have shown that the transcriptional coactivators, PGC-1α and β, are required for the surge in mitochondrial biogenesis which occurs at birth in heart and other mitochondrial-rich tissues. However, this work did not define the role played by the PGC-1 coactivators during postnatal development and in the adult heart. To this end, we generated mice with both whole body deletion of PGC-1α and heart/muscle-specific “knock-down” (KD) of PGC-1β via Cre-recombinase driven by the MCK promoter (PGC-1α-/-βf/fMCK-Cre). Echocardiographic studies demonstrated that the PGC-1α-/-βf/fMCK-Cre mice developed a cardiomyopathy beginning at 1 wk of age that increased in severity during the subsequent 8 wks leading to death. Electron microscopic analysis of PGC-1α-/-βf/fMCK-Cre myocardium revealed profound and progressive mitochondrial structural derangements including heterogeneity in size (fragmented and elongated mitochondria) and reduced volume density beginning in the early postnatal period, despite a relatively normal perinatal biogenic response. Expression of genes involved in mitochondrial dynamics were assessed at 8 weeks of age in PGC-1α-/-βf/fMCK-Cre hearts. Expression of the mitochondrial fusion gene, Mfn1, was diminished (mean decrease of 71%), along with a marked reduction of Mfn1 protein levels (76% decrease) in PGC-1α-/-βf/fMCK-Cre hearts compared to controls. Other genes involved in mitochondrial fusion, Mfn2 and Opa1, and fission, Drp1, were significantly, but less severely, reduced in the PGC-1α-/-βf/fMCK-Cre hearts (43%, 42%, and 45%, respectively). State 3 respiration in mitochondria was significantly reduced in PGC-1α-/-βf/fMCK-Cre hearts to 33% at 4 wks of age. Overexpression of PGC-1α or β in isolated primary neonatal rat cardiac myocytes (NRCM) induced Mfn1 gene expression by 2.5-fold, while KD of PGC-1α and β caused a 42% reduction in Mfn1 mRNA levels. Taken together, these results suggest that PGC-1 coactivators are required for the normal postnatal maturation of mitochondria in heart, including control of mitochondrial fusion and fission.
- © 2011 by American Heart Association, Inc.