Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy

Mengyi Wang; Shiwu Zhang; Jinwei Tian; Fan Yang; He Chen; Shuzhi Bai; Jiaxin Kang; Kemiao Pang; Jiayi Huang; Mingjie Dong; Shiyun Dong; Zhen Tian; Shaohong Fang; Huitao Fan; Fanghao Lu; Bo Yu; Shuijie Li; Weihua Zhang

doi:10.1002/advs.202406695

Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy

Adv Sci (Weinh). 2024 Nov 4:e2406695. doi: 10.1002/advs.202406695. Online ahead of print.

Authors

Mengyi Wang^{1

2

3}, Shiwu Zhang^{1

3}, Jinwei Tian^{1

2

4}, Fan Yang^{1

3

4}, He Chen⁵, Shuzhi Bai³, Jiaxin Kang³, Kemiao Pang³, Jiayi Huang³, Mingjie Dong⁶, Shiyun Dong³, Zhen Tian³, Shaohong Fang^{1

4}, Huitao Fan^{7

8

9

10}, Fanghao Lu³, Bo Yu^{1

4

11}, Shuijie Li^{12

13}, Weihua Zhang^{1

2

3

4}

Affiliations

¹ Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu ROAD, Harbin, 150086, China.
² Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, 150000, China.
³ Department of Pathophysiology, Harbin Medical University, Harbin, 150000, China.
⁴ Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, 150000, China.
⁵ Department of Forensic Medicine, Harbin Medical University, Harbin, 150000, China.
⁶ College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150000, China.
⁷ Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
⁸ Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
⁹ NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
¹⁰ Key Laboratory of Hepatosplenic Surgery of Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
¹¹ State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, 150000, China.
¹² State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150000, China.
¹³ Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti-Tumor Drugs, Harbin, 150000, China.

PMID: 39495652
DOI: 10.1002/advs.202406695

Abstract

Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron-sulfur (Fe-S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S-sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H₂S) supplementation restores NFS1 S-sulfhydration at cysteine 383 residue, thereby enhancing Fe-S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe-S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes.

Keywords: PARthanatos; cysteine desulfurase (NFS1); diabetic cardiomyopathy (DCM); hydrogen sulfide (H2S); iron–sulfur (Fe–S) cluster.

Grants and funding

82270359/National Natural Science Foundation of China