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Peer-reviewedCC BY 4.0Cell Death Discovery

Palmitoylation-driven upregulation of NKAα2 improves diabetic cardiomyopathy: a role for the fumarate hydratase/fumarate metabolic pathway

  • Xi-Xi Lu1,2,3
  • Yu-Yan Feng1,2,3
  • Le Yang1,2,3
  • Ming-Tao Yang1
  • Hao-Ting Liu1
  • Si-Ping Xiong4
  • Jian Zhu1
  • Ping-Xi Xiao5,6
  • Hai-Jian Sun2,3,7
  • Qing-Bo Lu1
7 affiliations
  1. 1Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China
  2. 2MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, China
  3. 3Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu China
  4. 4Department of Pathology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong China
  5. 5Department of Cardiology, Shanghai Dongfang Hospital, Shanghai Tongji University School of Medicine, Shanghai, China
  6. 6Present Address: Department of Cardiology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
  7. 7State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China
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Abstract

The sodium pump Na⁺/K⁺-ATPase (NKA) plays an essential role in maintaining cellular ion homeostasis. Dysregulation of its α2 subunit (NKAα2) has been implicated in cardiovascular and metabolic diseases, yet its contribution to diabetes-induced cardiac dysfunction remains poorly defined. Therefore, this study aimed to elucidate the role of NKAα2 in diabetic cardiomyopathy (DCM). We performed gain-of-function experiments to investigate the effects of NKAα2 on DCM-associated pathological processes. Both in vivo mouse models and in vitro cardiomyocyte systems were employed to ensure mechanistic consistency. We found that both NKA activity and NKAα2 protein, rather than its transcriptional level, were significantly downregulated in the hearts of diabetic mice and high glucose/palmitic acid (HG/PA)-incubated NRCMs. Cardiac-specific overexpression of NKAα2 markedly alleviated myocardial injury and improved cardiac function in diabetic mice. Consistently, NKAα2 overexpression attenuated HG/PA–induced hypertrophy and apoptosis in primary neonatal rat cardiomyocytes (NRCMs). Mechanistically, ATP-1 mediated de-palmitoylation increased NKAα2 in the mitochondrial-enriched fraction, where it interacted with E3 ubiquitin protein ligase 1 (MUL1), which was responsible for NKAα2 ubiquitination and degradation. Metabolomic analyses revealed that NKAα2 downregulation dissociated Mul1 from fumarate hydratase (FH), leading to increased FH expression and decreased intracellular fumarate levels. Exogenous fumarate administration mimicked the cardioprotective effects of NKAα2 overexpression and mitigated the damage caused by NKAα2 deficiency in HG/PA-treated cardiomyocytes. Overexpression of FH blocked the effects of NKAα2 on diabetic cardiac dysfunction. Collectively, these findings identify NKAα2 as a critical regulator in DCM. These results also underscore the requirement of tightly controlled FH activity and fumarate metabolism for NKAα2-dependent cardioprotection.

A diagram illustrating the molecular mechanism of the NKAα2/FH/fumarate metabolic axis in the development of DCM.

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Cite

BibTeXRIS
BibTeX
@article{lu2026palmitoylationdriven,
  title = {{Palmitoylation-driven upregulation of NKAα2 improves diabetic cardiomyopathy: a role for the fumarate hydratase/fumarate metabolic pathway}},
  author = {Xi-Xi Lu and Yu-Yan Feng and Le Yang and Ming-Tao Yang and Hao-Ting Liu and Si-Ping Xiong and Jian Zhu and Ping-Xi Xiao and Hai-Jian Sun and Qing-Bo Lu},
  journal = {Cell Death Discovery},
  year = {2026},
  month = jul,
  doi = {10.1038/s41420-026-03275-9},
  url = {https://doi.org/10.1038/s41420-026-03275-9},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Palmitoylation-driven upregulation of NKAα2 improves diabetic cardiomyopathy: a role for the fumarate hydratase/fumarate metabolic pathway
AU  - Xi-Xi Lu
AU  - Yu-Yan Feng
AU  - Le Yang
AU  - Ming-Tao Yang
AU  - Hao-Ting Liu
AU  - Si-Ping Xiong
AU  - Jian Zhu
AU  - Ping-Xi Xiao
AU  - Hai-Jian Sun
AU  - Qing-Bo Lu
PY  - 2026
DA  - 2026/07/29
JO  - Cell Death Discovery
DO  - 10.1038/s41420-026-03275-9
UR  - https://doi.org/10.1038/s41420-026-03275-9
AB  - The sodium pump Na⁺/K⁺-ATPase (NKA) plays an essential role in maintaining cellular ion homeostasis. Dysregulation of its α2 subunit (NKAα2) has been implicated in cardiovascular and metabolic diseases, yet its contribution to diabetes-induced cardiac dysfunction remains poorly defined. Therefore, this study aimed to elucidate the role of NKAα2 in diabetic cardiomyopathy (DCM). We performed gain-of-function experiments to investigate the effects of NKAα2 on DCM-associated pathological processes. Both in vivo mouse models and in vitro cardiomyocyte systems were employed to ensure mechanistic consistency. We found that both NKA activity and NKAα2 protein, rather than its transcriptional level, were significantly downregulated in the hearts of diabetic mice and high glucose/palmitic acid (HG/PA)-incubated NRCMs. Cardiac-specific overexpression of NKAα2 markedly alleviated myocardial injury and improved cardiac function in diabetic mice. Consistently, NKAα2 overexpression attenuated HG/PA–induced hypertrophy and apoptosis in primary neonatal rat cardiomyocytes (NRCMs). Mechanistically, ATP-1 mediated de-palmitoylation increased NKAα2 in the mitochondrial-enriched fraction, where it interacted with E3 ubiquitin protein ligase 1 (MUL1), which was responsible for NKAα2 ubiquitination and degradation. Metabolomic analyses revealed that NKAα2 downregulation dissociated Mul1 from fumarate hydratase (FH), leading to increased FH expression and decreased intracellular fumarate levels. Exogenous fumarate administration mimicked the cardioprotective effects of NKAα2 overexpression and mitigated the damage caused by NKAα2 deficiency in HG/PA-treated cardiomyocytes. Overexpression of FH blocked the effects of NKAα2 on diabetic cardiac dysfunction. Collectively, these findings identify NKAα2 as a critical regulator in DCM. These results also underscore the requirement of tightly controlled FH activity and fumarate metabolism for NKAα2-dependent cardioprotection.  A diagram illustrating the molecular mechanism of the NKAα2/FH/fumarate metabolic axis in the development of DCM.
SN  - 2058-7716
ER  -