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

Mar 10, 2026Molecular therapy : the journal of the American Society of Gene Therapy

Activating a key gene to increase natural mitochondria and improve heart function after a heart attack

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Abstract

Transcriptional activation of PPARGC1A using CRISPRa increases cellular mitochondria and improves heart function after myocardial infarction.

Insufficient energy supply from impaired mitochondria is linked to heart failure following a heart attack.
Supraphysiological levels of PPARGC1A can lead to adverse heart remodeling and dysfunction.
CRISPR activation technologies allow for controlled expression of genes like PPARGC1A.
Activating PPARGC1A increases mitochondrial numbers and enhances ATP production in human heart cells.
In vivo targeting of PPARGC1A using CRISPRa improves heart ejection fraction in a model of acute heart attack.
This approach boosts mitochondrial function in both healthy and heart failure-affected human hearts.

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Insufficient energy supply due to impaired mitochondria has emerged as a key pathological factor in the development of heart failure (HF) after myocardial infarction (MI). Unfortunately, no current therapeutic strategies directly augment myocardial energy production. While mitochondrial biogenesis is orchestrated by the activity of multiple genes, activation of PPARGC1A, a key regulator, can increase cellular mitochondria; however, supraphysiological levels of PPARGC1A result in adverse tissue remodeling and heart dysfunction. CRISPR activation (CRISPRa) technologies present a unique opportunity to address these shortcomings, as they enable tunable control over endogenous target gene expression. Here, we demonstrate that transcriptional activation of PPARGC1A using CRISPRa increases cellular mitochondria in human cell types. This effect is mediated through the activation of transcriptional programs driving mitochondrial biogenesis, mitochondrial function, and cellular bioenergetics. These activated transcriptional programs synergize to increase ATP production and reserve capacity in human cardiomyocytes. CRISPRa targeting of PPARGC1A in vivo increases cardiac mitochondria to recover heart ejection fraction in an acute MI model. Furthermore, CRISPRa acts on the adult human heart to increase PPARGC1A protein and cellular mitochondria, elevating mitochondrial function in both normal and HF-diagnosed hearts. These results provide the first proof of concept that endogenous gene activation via CRISPRa can improve heart function after MI.