Abstract
Metabolic adaption is crucial for the heart to sustain its contractile activity under various physiological and pathological conditions. At the molecular level, the changes in energy demand impinge on the expression of genes encoding for metabolic enzymes. Among the major components of an intricate transcriptional circuitry, peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) plays a critical role as a metabolic sensor, which is responsible for the fine-tuning of transcriptional responses to a plethora of stimuli. Cumulative evidence suggests that energetic impairment in heart failure is largely attributed to the dysregulation of PGC-1α. In this review, we summarize recent studies revealing how PGC-1α is regulated by a multitude of mechanisms, operating at different regulatory levels, which include epigenetic regulation, the expression of variants, post-transcriptional inhibition, and post-translational modifications. We further discuss how the PGC-1α regulatory cascade can be impaired in the failing heart.
Highlights
Peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) belongs to a small family of transcriptional coactivators, including PGC-1β and PGC-1-related coactivator (PRC), which possess a common function in mitochondrial physiology
We demonstrated that Sirtuin 1 (Sirt1) deacetylates histone H3K9 in the PGC-1α promoter in the failing heart [28] (Figure 1), which presumably leads to inactivation of the gene
We demonstrated that PGC-1α recruits RNA polymerase II (PolII) to the promoters of metabolic genes, which was dissipated in the failing heart [25] (Figure 1C)
Summary
Peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) belongs to a small family of transcriptional coactivators, including PGC-1β and PGC-1-related coactivator (PRC), which possess a common function in mitochondrial physiology. Other studies, including ours, suggest that the expression levels of PGC-1α per se cannot always explain downregulation of PGC-1α target genes in the failing heart [23,24,25]. A downregulation of PGC-1α and the reduced mitochondrial respiration capacity in the failing heart were associated with an elevated level of H3K9me3, a marker of gene repression, on the PGC-1α promoter [27] (Figure 1A, bottom).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
