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SAP30BP aggravates mitochondrial-related ferroptosis in diabetic cardiomyopathy by regulating MFN2-ACSL4 axis
Tong Zhao1, Chen Chen1, Wenjie Zhao1
1Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, 150081, China; State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin, 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China.
Abstract:
Ferroptosis is characterized by iron overload and uncontrolled lipid peroxidation, which plays a substantial role in the development of diabetic cardiomyopathy (DCM). However, the exact factor responsible for inducing ferroptosis in DCM has not been fully elucidated. SAP30 binding protein (SAP30BP), a member of the HCNGP family, functions as a transcription regulator. Our research reveals a significant increase in SAP30BP expression in the hearts of DCM mice and cardiomyocytes treated with high glucose (HG). Knockdown of SAP30BP ameliorated cardiac dysfunction and inhibited ferroptosis and mitochondrial damage in DCM hearts. At the cellular levels, transfection of si-SAP30BP suppressed ferroptosis, as evidenced by the reduced oxidative stress, iron overload and lipid peroxidation. RNA-seq and GEO database analysis suggested that mitochondrial dynamics contributed to SAP30BP induced ferroptosis. Mechanistically, SAP30BP inhibited the transcription of MFN2 through HDAC1-mediated histone deacetylation, leading to mitochondrial dynamic disruption and dysfunction. This process ultimately hindered the mitochondrial translocation of ACSL4 and mitochondria-associated ferroptosis. Collectively, our findings demonstrate the therapeutic benefits of SAP30BP knockdown in DCM by effectively suppressing mitochondria-associated ferroptosis through the MFN2-ACSL4 pathway. These results provide new mechanistic insights and a basis for developing mitochondria and ferroptosis targeting therapies for DCM.
Insights
SAP30 binding protein (SAP30BP) drives ferroptosis in diabetic cardiomyopathy. Inhibiting SAP30BP protects the heart by preventing iron overload and lipid peroxidation, offering a potential therapeutic strategy for DCM.
Area of Science:
- Cardiovascular Biology
- Cell Death Mechanisms
- Molecular Endocrinology
Background:
- Diabetic cardiomyopathy (DCM) involves ferroptosis, characterized by iron overload and lipid peroxidation.
- The specific inducer of ferroptosis in DCM remains unclear.
- SAP30 binding protein (SAP30BP) is a transcription regulator implicated in cellular processes.
Purpose of the Study:
- To investigate the role of SAP30BP in ferroptosis within diabetic cardiomyopathy.
- To elucidate the molecular mechanisms by which SAP30BP influences ferroptosis in DCM.
- To assess the therapeutic potential of targeting SAP30BP in DCM.
Main Methods:
- Analysis of SAP30BP expression in DCM mouse models and high glucose-treated cardiomyocytes.
- Investigating the effects of SAP30BP knockdown on cardiac function, ferroptosis, and mitochondrial integrity.
- Utilizing RNA-sequencing and database analysis to identify pathways involved in SAP30BP-induced ferroptosis.
- Examining the interaction between SAP30BP, HDAC1, MFN2, and ACSL4.
Main Results:
- SAP30BP expression is significantly elevated in DCM hearts and high glucose-treated cardiomyocytes.
- SAP30BP knockdown alleviates cardiac dysfunction and inhibits ferroptosis and mitochondrial damage in DCM.
- SAP30BP suppresses ferroptosis by inhibiting MFN2 transcription via HDAC1, disrupting mitochondrial dynamics and ACSL4 translocation.
- Mitochondrial dynamics are identified as a key contributor to SAP30BP-induced ferroptosis.
Conclusions:
- SAP30BP promotes mitochondria-associated ferroptosis in DCM through the MFN2-ACSL4 pathway.
- Targeting SAP30BP offers a promising therapeutic approach for DCM by mitigating ferroptosis.
- These findings provide novel mechanistic insights into DCM pathogenesis and ferroptosis regulation.
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