A Role for Peroxisome Proliferator-Activated Receptor γ Coactivator-1 in the Control of Mitochondrial Dynamics During Postnatal Cardiac Growth

Abstract

Rationale Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high capacity ATP production in heart. The transcriptional coactivators, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) α and β have been shown to regulate mitochondrial biogenesis in heart at the time of birth. The function of the PGC-1 coactivators in heart after birth is incompletely understood. Objective To assess the role of the PGC-1 coactivators during postnatal cardiac development and in the adult heart in mice. Methods and Results Conditional gene targeting was used in mice to explore the role of the PGC-1 coactivators during postnatal cardiac development and in adult heart. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion [mitofusin 1 (Mfn1), optic atrophy 1 (Opa1)] and fission [dynamin-related protein 1 (Drp1), fission protein 1 (Fis1)] was altered in hearts of PGC-1α/β-deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α (ERRα) upon a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that the PGC-1 coactivators are required for high level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in adult heart. Conclusion These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics.

Cardiac nuclear receptors: architects of mitochondrial structure and function

“…KLF4 synergizes with ERRα to activate target genes and is necessary for normal mitochondrial biogenesis and function in the heart (49). (71,75). Surprisingly, cardiac-specific, inducible deletion of Ppargc1b on a systemic Ppargc1a-null background in adult mice results in a rather minimal mitochondrial structural phenotype without overt cardiac dysfunction.…”

“…Surprisingly, cardiac-specific, inducible deletion of Ppargc1b on a systemic Ppargc1a-null background in adult mice results in a rather minimal mitochondrial structural phenotype without overt cardiac dysfunction. However, the hearts of these mice exhibit a marked and global reduction in expression of nuclear-encoded mitochondrial genes and reduced State 3 respiration (71,76). Compared with the neonatal phenotype, the minimal cardiac phenotype of adult PGC-1α/β deficiency may reflect relatively low rates of mitochondrial turnover and replacement (mitophagy) in the normal adult heart.…”

“…Thus, PGC-1 functions as the "conductor" of a coordinated mitochondrial gene regulatory program (Figure 2). PGC-1 transgenic and gene deletion studies in mice have provided significant insight into the role of these coregulators in the development of the high-capacity mitochondrial system in heart (63,(68)(69)(70)(71). Such studies demonstrate that PGC-1α is necessary for maximal ATP synthesis and FAO, likely working largely with the ERRs (72).…”

The role of mitochondria in cardiac development and protection

“…Instead, the physiologically less responsive PPAR coactivator PGC-1 is dramatically upregulated during postnatal hypertrophy, concomitantly with an increase in the NEM gene expression levels. Intriguingly, neither one of the PGC-1s is required later for the maintenance of mitochondrial mass in the adult mouse [62]. While also the CREB family proteins CREM, CREBL2 and CREB3L2 as well as the nuclear transcription factor STAT3 might play a role in the upregulation of mitochondrial components during the postnatal development, none of the NRF genes seems to be involved in the process [61].…”

“…Both age-related decline in cardiac contractility as well as developing cardiomyopathy result in specific loss of IFM function [71,138], which might be possible to counteract by promoting mitochondrial biogenesis, resulting not only in increased OXPHOS but also activating mitochondrial fission [4,62]. Interestingly, in mitochondrial fusion-deficient mice already a change to high-fat diet was enough to alter cardiac metabolism and prevent the development of cardiomyopathy [75].…”