Journal Article

Acid sphingomyelinase promotes diabetic cardiomyopathy via disruption of mitochondrial calcium homeostasis

Tang, Yongzhong, Wei, Yu, Meng, Jiahui, Yu, Li, Ji, Yang, Fang, Wei-Jin

2025

Overview

Background Impaired Ca 2+ handling is involved in diabetic cardiomyopathy (DCM) progression. The activation of acid sphingomyelinase (ASMase) stimulated cardiomyocytes apoptosis and caused DCM. Here, we aimed to investigate whether ASMase regulates mitochondrial Ca 2+ homeostasis by acting on mitochondrial calcium uptake 1 (MICU1) and mitochondria-associated endoplasmic reticulum membranes (MAMs) formation to induce apoptosis during DCM. Methods and results We established a type 2 diabetes model by combining high-fat diet (HFD) with streptozotocin (STZ) injection in wild-type and cardiomyocyte-specific ASMase deletion (ASMase Myh6KO ) mice. ASMase deletion restored HFD/STZ-induced cardiac dysfunction, remodeling, myocardial lipid accumulation and apoptosis. Single cell sequencing and Gene ontology (GO) enrichment analysis pointed to “cardiac muscle contraction” and “positive regulation of mitochondrial calcium ion concentration”, which were confirmed by high glucose (HG, 30 mM) and palmitic acid (PA, 200 μM) induced mitochondrial Ca 2+ overload in H9c2 cell lines at time dependence, accompanied by the upregulation of ASMase and MICU1 protein expressions. The similar effects were noted in ASMase overexpressed cardiomyocytes. Interestingly, endoplasmic reticulum (ER) Ca 2+ level was decreased at the corresponding time, suggesting that increased mitochondrial Ca 2+ level may be derived from ER. Notably, enhanced MAMs formation was found in HG + PA treated H9c2 cells, accompanied by blocked autophagy, similar results were obtained in ASMase overexpressing cells or HFD/STZ hearts. Loss of ASMase prevented HFD/STZ or HG + PA incubation induced cardiac hypertrophy, mitochondrialCa 2+ overload, ROS production, autophagy blockage and MICU1 upregulation. Conclusions HFD/STZ-induced ASMase upregulation enhances MAMs formation, promoting mitochondrial Ca 2+ overload through MICU1 activation, leading to ROS generation, autophagy blockage and apoptosis in DCM. Therefore, targeting ASMase-MICU1 pathway emerges as a potential therapeutic approach for managing DCM. Graphical Abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Angiology / Animals / Antigens / Apoptosis / ASMase / Autophagy / Calcium (mitochondrial) / Calcium (reticular) / Calcium - metabolism / Calcium homeostasis / Calcium influx / Calcium Signaling / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cardiac muscle / Cardiology / Cardiomyocytes / Cardiomyopathy / Cell Line / Cell lines / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - enzymology / Diabetes Mellitus, Experimental - genetics / Diabetes Mellitus, Experimental - pathology / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - enzymology / Diabetes Mellitus, Type 2 - genetics / Diabetic Cardiomyopathies - enzymology / Diabetic Cardiomyopathies - etiology / Diabetic Cardiomyopathies - genetics / Diabetic Cardiomyopathies - pathology / Diabetic cardiomyopathy / Diet, High-Fat / Endoplasmic reticulum / Endoplasmic Reticulum - enzymology / Endoplasmic Reticulum - pathology / Glucose / High fat diet / Homeostasis / Hypertrophy / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mice, Knockout / Microscopy / MICU1 / Mitochondria / Mitochondria, Heart - enzymology / Mitochondria, Heart - pathology / Mitochondrial calcium homeostasis / Mitochondrial Membrane Transport Proteins / Mortality / Muscle contraction / Myocytes, Cardiac - enzymology / Myocytes, Cardiac - pathology / Oxidative stress / Palmitic acid / Pathogenesis / Physiology / Rats / Sphingomyelin phosphodiesterase / Sphingomyelin Phosphodiesterase - deficiency / Sphingomyelin Phosphodiesterase - genetics / Sphingomyelin Phosphodiesterase - metabolism / Streptozocin / Up-regulation / Ventricular Remodeling