CRISPR/Cas-based activation of PPARGC1A boosts endogenous mitochondria and enhances cardiac function and recovery after myocardial infarction

Although current therapeutic strategies of revascularization and afterload reduction have been transformative, no strategy directly augments myocardial energy production. In mammalian cells, mitochondrial biogenesis is orchestrated by the activity of multiple genes encoded by both the nuclear and mitochondrial genomes.

While the activation of PPARGC1A, a key driver of mitochondrial biogenesis, can increase cellular mitochondria, supraphysiological levels of PPARGC1A result in adverse tissue remodeling and heart function. CRISPR activation (CRISPRa) technologies present a unique opportunity to address these shortcomings, as they enable tunable control over endogenous target gene expression in cells and in vivo. Here, we demonstrate that transcriptional activation of PPARGC1A using CRISPRa increases cellular mitochondria in diverse human cell types.