Year: 2024
Type: article
Abstract: Background: Septic cardiomyopathy(SCM) is notorious for its high mortality. Our previous study on SCM patients after thoracic surgery demonstrated over 50% mortality and brain natriuretic peptide(BNP) was the best clinical marker in predicting SCM after surgery. Yet, there are no efficacious therapies except for fluid rescucitation, catecholamine and antibiotics. Mitochondrial dysfunction is a key contributor to septic cardiomyopathy. MAPL (mitochondrial anchored protein ligase) is a small ubiquitin-like modifier (SUMO) E3 ligase, which is involved in mitochondrial dynamics, inflammation and cell apoptosis. However, the role of MAPL in septic cardiomyopathy remains unknown.Methods: LPS treatment in H9C2 cardiomyocytes and cecal ligation perforation (CLP) in mice were applied to induce condition mimicking septic cardiomyopathy. shRNA-mediated MAPL knockdown was performed in H9C2 cells. Cardiomyocyte-specific MAPL knockout mice was established by generating MAPL flox/flox mice followed by crossbreeding with Myh6Cre mice.Results: The protein level of MAPL was upregulated in heart tissues of mice and H9C2 cardiomyocytes after CLP challenge and LPS stimulation, respectively. MAPL deficiency or knockdown ameliorated CLP-induced cardiac injury/dysfunction and systematic inflammation or LPS-induced cardiomyocytes apoptosis. In addition, MAPL-knockout or -knockdown septic cardiomyocytes exhibited less mitochondrial structure abnormalities, increased ATP production, increased mitochondrial membrane potential (MMP) and reduced autophagy, compared with the control group. The protein level of Drp1(dynamin-related protein 1), an essential protein for mitochondrial fission, in heart tissues and H9C2 cardiomyocytes was increased over time under sepsis conditions. Mechanistically, MAPL mediates SUMOylation of mitochondrial proteins by SUMO1 rather than SUMO2/3. In particular, the SUMOylation of Drp1 was increased after CLP challenge or LPS stimulation, and was suppressed by MAPL knockout or knockdown. Thus, Drp1 SUMOylation may contribute to its protein level elevation under sepsis conditions.Conclusions: Our results reveal the role MAPL in septic cardiomyopathy and the underlying mechanism involving MAPL-mediated Drp1 SUMOylation and the subsequent Drp1-mediated mitochondrial fission. Targeting MAPL may represent a therapeutic strategy for patients with septic cardiomyopathy.
Institutions: Shanghai Jiao Tong University, Shanghai Chest Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,790
OpenAlex ID: W4404223806