2. Academic Validation
  3. PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production

PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production

  • EMBO Rep. 2024 Mar 13. doi: 10.1038/s44319-024-00110-z.
Cheng Chen # 1 2,  Qianyu Liu # 3,  Wenjie Chen # 4,  Zhiyuan Gong 5,  Bo Kang 6,  Meihua Sui 7,  Liming Huang 8,  Ying-Jie Wang 9 10
Affiliations

Affiliations

  • 1 Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang, 312000, China.
  • 2 School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 3 College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 4 Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
  • 5 Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
  • 7 School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. suim@zju.edu.cn.
  • 8 Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang, 312000, China. 0622122@zju.edu.cn.
  • 9 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China. yingjiewang@zju.edu.cn.
  • 10 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. yingjiewang@zju.edu.cn.
  • # Contributed equally.
PMID: 38480845 DOI: 10.1038/s44319-024-00110-z
Abstract

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and Oxidative Phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism Enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK Inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial Oxidative Phosphorylation (mtOXPHOS) and Reactive Oxygen Species (ROS) production that triggered Autophagy, DNA damage, and Apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

Keywords

Electron Transport Chain Complex; Human Naive Pluripotency; PRODH; Reactive Oxygen Species; mtOXPHOS.

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