Impact of SARS-CoV-2 infection on the mitochondrial network in human pluripotent stem cell-derived cardiomyocytes

Abstract

Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has been associated with cardiovascular complications, including cardiac failure, arrhythmias, and acute coronary syndromes, particularly among hospitalized patients. Elevated levels of both troponin and cell-free mitochondrial DNA in the bloodstream have been identified as biomarkers, correlating with the severity of the disease. These markers suggest that SARS-CoV-2 may induce damage to both cardiac cells and mitochondria. Given the crucial role of mitochondria in maintaining the physiological functions of cardiomyocytes, we aim to investigate the impact of SARS-CoV-2 on both cardiac cells and their mitochondrial function.

Objective

We aim to explore whether SARS-CoV-2 can directly infect cardiomyocytes and subsequently examine the extent of mitochondrial network disruptions. Finally, we will investigate the downstream consequences of these mitochondrial alterations, particularly metabolic processes and innate immune responses, which are closely tied to SARS-CoV-2 infection.

Method

We used human pluripotent stem cell-derived cardiomyocytes (HPSC-CMs) as a model to study SARS-CoV-2 infection. Infection was assessed through microscopy and viral RNA detection. We also examined changes in cellular, nuclear, and mitochondrial morphology following infection using advanced imaging techniques. Additionally, we measured alterations in RNA expression of inflammatory markers and mitochondrial genes. Finally, we used a non-cardiac cell line to confirm the ability of SARS-CoV-2 to induce mitochondrial disruptions and to investigate the viral and cellular protein factors involved in this process.

Results

Following SARS-CoV-2 infection, we confirmed viral genome presence in HPSC-CMs and observed Troponin+ and Spike+ cells. We showed that infection led to an increase of inflammation markers and a morphological perturbation of the HPSC-CMs. Both cardiac and non-cardiac cell line showed signs of mitochondrial network perturbation. We identify ORF9b, an antagonist of innate immune response, as a viral candidate for this perturbation.

Conclusion

These findings confirm that SARS-CoV-2 can directly infect cardiomyocytes, triggering an inflammatory response. The virus targets mitochondria, which play a dual role as both the primary energy source and a reservoir of compounds utilized by the virus for replication, as well as a platform for initiating innate immune responses. This interaction may provide a key mechanism underlying the cardiac injuries observed during SARS-CoV-2 infection.