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.