SARS-CoV-2-infected cardiomyocytes exhibit upregulated necroptosis, but no evidence of mitochondrial permeability transition

作者：Carina Gross, Shambhabi Chatterjee, Benjamin E. Nilsson-Payant, Stevan D. Stojanović, Helenie Kefalakes, Christian Bär, Thomas Thum, Thomas Pietschmann, Johann Bauersachs, Georgios Amanakis · 发表于：Journal of Molecular and Cellular Cardiology Plus · 年份：2025 · DOI：10.1016/j.jmccpl.2025.100833 · 被引用次数：1 · 研究领域：Cell death mechanisms and regulation、Mitochondrial Function and Pathology、COVID-19 Clinical Research Studies

Cardiac involvement in patients infected with COVID-19, in terms of myocarditis and troponin release, is associated with higher mortality. However, the underlying mechanisms are poorly understood. Infection of cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) with a wild-type variant of SARS-CoV-2 exhibited a cardiotoxic effect. We examined whether elevated intramitochondrial calcium causes opening of the mitochondrial permeability transition pore (mPTP) leading to cell death. The mPTP inhibitor Cyclosporine A (CsA) did not improve viability, and phosphorylation levels of pyruvate dehydrogenase (PDH) remained similar pre- and post-infection, likely suggesting no substantial alteration of the intramitochondrial calcium level. Also, the protein expression of mitochondrial respiratory complexes did not change after SARS-CoV-2 infection. Next, we examined whether cell death is related to necroptosis or pyroptosis upregulation. The phosphorylation level of receptor-interacting protein kinase 3 (RIP3) was elevated post-infection with SARS-CoV-2 while phosphorylation of mixed lineage kinase domain (MLKL)-S358 remained unaltered. This pattern may point toward an alternative regulation of necroptosis. Chemical inhibition of necroptosis (Necrostatin-1) and pyroptosis (MCC950) did not confer any protection. Notably, the phosphorylation of RIP3 under Necrostatin-1 was still elevated, suggesting that autophosphorylation of RIP3 may be a possible confounder. Our d...