Multiple Levels of PGC-1α Dysregulation in Heart Failure

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.

Keywords: PGC-1α; cardiac metabolism; epigenetics; heart failure; histone methylation; mitochondria; transcriptional control.

Figure 1

Multiple levels of PGC-1α signaling dysregulation in heart failure. Dysregulation of the PGC-1α regulatory cascade can occur at the level of gene expression (A), post-translational modifications (PTM) (B), and PGC-1α function (C). (A) At the gene expression level, the PGC-1α cascade can be modulated via histone modifications ((de)methylation and (de)acetylation), DNA (de)methylation, by various transcription factors [TFs, reviewed in (17)], and via post-transcriptional inhibition of the PGC-1α gene by non-coding (nc) RNAs. The histone methyltransferase Smyd1 increases promoter activity of PGC-1α through regulating the enrichment of the H3K4me3 levels (a gene activation mark) (26). In different animal models of heart failure, reduced expression of PGC-1α was associated with increased H3K9me3 level (a gene repression mark) (27) or a decreased level of H3K9Ac (a gene activation mark) (28). Sirtuin 1 (Sirt1) is a plausible histone deacetylase (HDAC) for gene repression of PGC-1α under pressure overload (28), but this remains to be established. DNA hypermethylation is known to suppress PGC-1α in the skeletal muscle (–31), but little is known about its role in PGC-1α regulation in the heart (32). The protein expression level of PGC-1α can be reduced through post-transcriptional inhibition by miRNAs, such as miR-22 (33) and miR-23a (34), but it is unknown whether small ncRNA-mediated PGC-1α repression occurs in heart failure. (B) PGC-1α activity is known to be regulated by posttranslational modifications (PTMs), including phosphorylation and acetylation [reviewed in (17)]. However, which PTMs of PGC-1α are specific for the development of heart failure remains unknown. Sirt1 deacetylases the PGC-1α protein (35), but it is not known whether this PTM is a part of PGC-1α dysregulation in the failing heart. (C) PGC-1α's transcriptional control of metabolic genes (i.e., Acadm, Sdha, Idh3a) largely depends on interaction with DNA-binding transcriptional factors (TF) [i.e., ERRs, PPARs, reviewed in (36)]. In addition, our recent study showed that PGC-1α recruits RNA Polymerase II (RNA PolII) to the promoter regions of PGC-1α target genes (25). Moreover, PGC-1α is dissociated from the promoters of its target genes and RNA PolII in the failing mouse heart (25). We propose that this alteration of PGC-1α behavior in the failing heart is secondary to a PTM of the PGC-1α protein, and intend to test this hypothesis in our future studies.

Figure 2

Transcriptional regulation of PGC-1α in the heart. Positive regulators for PGC-1α transcription include CREB, NFAT, MEF2, YY1, PPARδ, and PPARγ, whereas those negatively regulate PGC-1α include PPARα. These factors are activated (black arrows) or inhibited (blue lines) in the progression of heart failure. PGC-1α promotes its transcription through co-activation of MEF2 and YY1. Sirt1 either activates and inhibits PGC-1α, thereby positively and negatively regulates PGC-1α transcription.

Figure 3

Regulation in gene expression via histone acetylation and methylation. The protruding amino tails of histone proteins can undergo post-translational modifications that affect the expression of genes in close proximity. (A) Histone acetylation and deacetylation. Histone lysines are acetylated by histone acetyltransferases (HATs), which use acetyl-CoA as a cosubstrate. Histone deacetylases (HDACs) are grouped in four classes: Classes I, II, and IV are Zn²⁺-dependent and release acetate as a coproduct while sirtuins (class II HDACs) consume NAD⁺ and produce nicotinamide and O-acetyl-ADP-ribose. β-hydroxybutyrate (βOHB) is a ketone body and can inhibit class I and IIa HDACs, being structurally related to be well-known HDAC inhibitor butyrate (95). (B) Histone methylation and demethylation. Histones are methylated by histone methyltransferases (HMTs), which require S-adenosylmethionine (SAM) as a consubstrate, yielding S-adenosylhomocysteine (SAH), which is subsequently hydrolyzed to homocysteine and adenosine by SAH-hydrolase (96) Two classes of histone demethylases (HDMs) can remove a methyl group: Lysine-specific demethylase 1 (LSD1) requires the reduction of flavin adenine dinucleotide (FAD) (97), while the Jumonji C (JMJC) domain-containing lysine demethylases catalyze a different demethylation reaction that requires α-ketoglutarate (αKG), O², and Fe(II) (98). Fumarate and succinate, the intermediates in the TCA cycle, are the competitive inhibitors (99, 100). (C) Summary of modification sites of histone tails via acetylation and methylation. Other histone post-translational modifications include phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation citrullination, and biotinylation.

Figure 4

PGC-1α promoters and isoforms. The PGC-1α loci contains two promoters in the skeletal muscle: the canonical and alternative promoters [Reviewed in (128)]. Transcription initiated from the upstream alternative promoter of the PGC-1α gene results in the inclusion of new exons E1b or E1c, which generate PGC-1α-b and PGC-1α-c, respectively. The PGC-1α-b and PGC-1α-c proteins contain two distinct N-termini, which are different from the canonical PGC-1α-a derived from the exon (E1a) from the canonical promoter. Exercise increases the PGC-1α mRNA levels originated from the alternative promoter, which is correlated with the elevated H3K4me3 marks in the alternative promoter region of PGC-1α (110) (indicated with an orange star). However, it remains elusive what histone methylation modifiers are responsible for the increase of the H3K4me3 levels on the alternative protomer of PGC-1α by exercise. In our previous study, the enrichment of the H3K4me3 marks were assessed in the Smyd1-knockout mouse heart, which was reduced at the canonical promoter (~−1 kb from E1a, indicated with a yellow star), suggesting that Smyd1 regulates the expression of the PGC-1α-a mRNA isoform in the heart. It remains unknown whether the PGC-1α variants from the alternative promoter are involved in metabolic remodeling in the hypertrophied and failing heart.

Figure 5

Phenotypes of systemic PGC-1α knockout mice. Loss of PGC-1α leads to impaired energy homeostasis in a variety of organs (5, 21). Despite the reduced density and function of mitochondria in skeletal muscle (21) and abnormality in brown fat tissue with abundant accumulation of large lipid droplets (5), PGC-1α knockout mice are paradoxically lean and resistant to diet-induced obesity due to hyperactivity, resulted from the lesions in the striatum in the brain (5). Normal cardiac function (7, 8) and moderate systolic dysfunction (21) have been reported in two different lines of PGC-1α null mice. Nevertheless, both PGC-1α^−/− models show cardiac dysfunction in response to hemodynamic stress and metabolic challenge (8, 21). CNS, central nervous system.