Lithium downregulates phosphorylated acetyl‑CoA carboxylase 2 and attenuates mitochondrial fatty acid utilization and oxidative stress in cardiomyocytes

Chen,Pao-Huan; Lee,Ting-Wei; Liu,Shuen-Hsin; Huynh,Tin Van; Chung,Cheng-Chih; Yeh,Yung-Hsin; Kao,Yu-Hsun; Chen,Yi-Jen

doi:10.3892/etm.2024.12413

Lithium downregulates phosphorylated acetyl‑CoA carboxylase 2 and attenuates mitochondrial fatty acid utilization and oxidative stress in cardiomyocytes

Authors:
- Pao-Huan Chen
- Ting-Wei Lee
- Shuen-Hsin Liu
- Tin Van Huynh
- Cheng-Chih Chung
- Yung-Hsin Yeh
- Yu-Hsun Kao
- Yi-Jen Chen
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Affiliations: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Division of Cardiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, R.O.C.
Published online on: February 5, 2024 https://doi.org/10.3892/etm.2024.12413
Article Number: 126
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acetyl‑CoA carboxylase 2 plays a crucial role in regulating mitochondrial fatty acid oxidation in cardiomyocytes. Lithium, a monovalent cation known for its cardioprotective potential, has been investigated for its influence on mitochondrial bioenergetics. The present study explored whether lithium modulated acetyl‑CoA carboxylase 2 and mitochondrial fatty acid metabolism in cardiomyocytes and the potential therapeutic applications of lithium in alleviating metabolic stress. Mitochondrial bioenergetic function, fatty acid oxidation, reactive oxygen species production, membrane potential and the expression of proteins involved in fatty acid metabolism in H9c2 cardiomyocytes treated with LiCl for 48 h was measured by using a Seahorse extracellular flux analyzer, fluorescence microscopy and western blotting. Small interfering RNA against glucose transporter type 4 was transfected into H9c2 cardiomyocytes for 48 h to induce metabolic stress mimicking insulin resistance. The results revealed that LiCl at a concentration of 0.3 mM (but not at a concentration of 0.1 or 1.0 mM) upregulated the expression of phosphorylated (p‑)glycogen synthase kinase‑3 beta and downregulated the expression of p‑acetyl‑CoA carboxylase 2 but did not affect the expression of adenosine monophosphate‑activated protein kinase or calcineurin. Cotreatment with TWS119 (8 µM) and LiCl (0.3 mM) downregulated p‑acetyl‑CoA carboxylase 2 expression to a similar extent as did treatment with TWS119 (8 µM) alone. Moreover, LiCl (0.3 mM) inhibited mitochondrial fatty acid oxidation, improved coupling efficiency and the cellular respiratory control ratio, hindered reactive oxygen species production and proton leakage and restored mitochondrial membrane potential in glucose transporter type 4 knockdown‑H9c2 cardiomyocytes. These findings suggested that low therapeutic levels of lithium can downregulate p‑acetyl‑CoA carboxylase 2, thus reducing mitochondrial fatty acid oxidation and oxidative stress in cardiomyocytes.

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