DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Mitochondrial Dynamics

Background:

• DEAD-box helicase 17 (DDX17) is a transcriptional cofactor abundant in the myocardium.
• The precise role of DDX17 in cardiac function and heart failure (HF) remains largely unknown.

Purpose of the Study:

• To elucidate the function of DDX17 in cardiomyocytes and its involvement in the pathogenesis of heart failure.

Main Methods:

• Generation of cardiomyocyte-specific Ddx17-knockout (Ddx17-cKO) and transgenic (Ddx17-Tg) mice.
• Induction of cardiomyocyte injury and heart failure models.
• Analysis of autophagic flux, apoptosis, mitochondrial homeostasis, and the BCL6-DRP1 pathway.
• Correlation studies in human heart failure patient myocardial biopsies.

Main Results:

• DDX17 expression is downregulated in failing and injured hearts.
• Loss of DDX17 in cardiomyocytes exacerbates cardiac dysfunction, apoptosis, and HF progression.
• DDX17 inhibits BCL6-mediated repression of DRP1, thus preventing excessive mitochondrial fission.
• Restoring DDX17 preserves cardiac function and mitochondrial homeostasis.

Conclusions:

• DDX17 plays a protective role in the heart by maintaining mitochondrial homeostasis via the BCL6-DRP1 pathway.
• DDX17 deficiency contributes to heart failure pathogenesis.
• Targeting DDX17 may offer a therapeutic strategy for heart failure.