3C suppresses PINK1-mediated mitophagy and contributes to coxsackievirus B3 replication

Area of Science:

• Cardiology
• Virology
• Immunology
• Mitochondrial Biology

Background:

• Viral myocarditis (VM) is an inflammatory heart condition often caused by Coxsackievirus B3 (CVB3), leading to severe complications like heart failure.
• Mitophagy, a cellular process for removing damaged mitochondria mediated by PINK1, is crucial for maintaining heart health and antiviral defense.
• Current therapeutic options for CVB3-induced VM are limited, highlighting the need for novel treatment strategies.

Purpose of the Study:

• To investigate the role of mitophagy in CVB3-induced viral myocarditis using single-cell RNA sequencing.
• To elucidate the molecular mechanisms by which CVB3 affects mitophagy and host antiviral responses.
• To identify potential therapeutic targets for mitigating CVB3 pathogenesis and improving cardiac outcomes.

Main Methods:

• Single-cell RNA sequencing was employed to analyze cardiomyocyte pathology and mitophagy in CVB3-infected models.
• Investigated the impact of CVB3 infection on PINK1-dependent mitophagy and viral replication.
• Explored the interaction between CVB3 protein 3C, MAVS, PINK1, and the transcription factor FOSL1.

Main Results:

• CVB3 infection significantly impairs PINK1-dependent mitophagy, correlating with cardiomyocyte damage.
• CVB3 non-structural protein 3C degrades MAVS, disrupting the PINK1/MAVS regulatory loop and promoting viral replication.
• FOSL1 was identified as a novel negative regulator of PINK1 transcription, further exacerbating viral pathogenesis.

Conclusions:

• The 3C/FOSL1/PINK1/MAVS signaling axis is a critical determinant of CVB3 pathogenesis in viral myocarditis.
• Impaired mitophagy is a key feature of CVB3-induced cardiac injury.
• Targeting this signaling pathway offers a promising therapeutic avenue for viral myocarditis by restoring mitochondrial homeostasis and host-virus interaction.