PCSK9 Regulates Cardiac Mitochondrial Cholesterol by Promoting TSPO Degradation

Area of Science:

• Mitochondrial biology
• Cardiovascular research
• Cholesterol metabolism

Background:

• Mitochondrial cholesterol is vital for cardiac function, especially in heart failure.
• PCSK9 (proprotein convertase subtilisin-kexin type 9) deficiency in cardiomyocytes impairs heart function and mitochondrial cholesterol homeostasis.
• The precise mechanisms linking PCSK9 to mitochondrial cholesterol regulation in the heart are not fully understood.

Purpose of the Study:

• To elucidate the mechanisms by which PCSK9 influences mitochondrial cholesterol homeostasis in the heart.
• To investigate the role of translocator protein (TSPO) in the PCSK9-mediated regulation of cardiac mitochondrial function.
• To explore the therapeutic potential of targeting TSPO for heart failure treatment.

Main Methods:

• RNA sequencing and immunoblotting were used to analyze hearts from PCSK9-deficient and control mice.
• Transcriptome analysis compared human left ventricles with high versus low TSPO expression.
• Experiments in H9c2 cardiomyocytes and gene therapy in mice (AAV-shTSPO) were employed to study PCSK9/TSPO interactions and functional impacts.

Main Results:

• PCSK9 deficiency increased both gene and protein levels of TSPO, a mitochondrial cholesterol transporter, in mouse hearts.
• High TSPO expression in human hearts correlated with impaired mitochondrial and cardiac function.
• PCSK9 promotes TSPO degradation via a proteasomal pathway involving GRP78, maintaining mitochondrial cholesterol balance and function; TSPO downregulation improved cardiac function in PCSK9-deficient mice.

Conclusions:

• PCSK9 regulates cardiac mitochondrial cholesterol levels by controlling TSPO degradation.
• Targeting TSPO to modulate mitochondrial cholesterol presents a potential therapeutic strategy for heart failure.