SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics

Area of Science:

• Molecular Biology
• Cardiology
• Virology

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, leading to significant cellular damage.
• The precise molecular mechanisms underlying SARS-CoV-2-induced pathology, particularly in cardiac cells, remain incompletely understood.
• Understanding these mechanisms is crucial for developing effective therapeutics.

Purpose of the Study:

• To investigate the molecular basis of SARS-CoV-2-induced cellular damage.
• To identify specific viral proteins and cellular targets involved in disease progression.
• To explore potential therapeutic interventions targeting mitochondrial dysfunction.

Main Methods:

• Transcriptomic analysis of human peripheral blood mononuclear cells (PBMCs).
• Identification of SARS-CoV-2 protein interactions with mitochondrial components.
• Experimental manipulation using gene knockdown (CCDC58) and pharmacological inhibitors (cyclosporin A).

Main Results:

• SARS-CoV-2 proteins were found to target mitochondrial components, including cyclophilin D, SPG-7, ANT, ATP synthase, and CCDC58.
• Knockdown of CCDC58 or pretreatment with cyclosporin A improved mitochondrial calcium retention and bioenergetics.
• SARS-CoV-2 infection induced cardiomyocyte autophagy and cell death, which were mitigated by cyclosporin A.

Conclusions:

• SARS-CoV-2 viral proteins impair cardiomyocyte mitochondrial function, leading to disrupted calcium cycling and reduced cell viability.
• Targeting mitochondrial pathways, such as through mPTP inhibition, shows therapeutic potential against SARS-CoV-2-induced cardiac damage.