2. Academic Validation
  3. Mitochondrial dysfunction by glyoxalase 1 deficiency disrupts definitive endoderm and alveolar development of human pluripotent stem cells

Mitochondrial dysfunction by glyoxalase 1 deficiency disrupts definitive endoderm and alveolar development of human pluripotent stem cells

  • Exp Mol Med. 2025 Sep;57(9):1940-1950. doi: 10.1038/s12276-025-01524-y.
Suji Jeong # 1,  Hyebin Koh # 2 3,  Minje Kang 1,  Ji-Young Kim 1,  Roya Rasaei 1,  Woo Jin Kim 1 4,  Seon-Sook Han 1 4,  In Sun Hong 5,  Se-Ran Yang 6,  Jong-Hee Lee 7 8,  Seok-Ho Hong 9 10
Affiliations

Affiliations

  • 1 Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
  • 2 National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea.
  • 3 Department of Advance Bioconvergence, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Republic of Korea.
  • 4 Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea.
  • 5 Department of Biochemistry, School of Medicine, Gachon University, Incheon, Republic of Korea.
  • 6 Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
  • 7 National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea. jonglee@kribb.re.kr.
  • 8 Department of Advance Bioconvergence, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Republic of Korea. jonglee@kribb.re.kr.
  • 9 Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea. shhong@kangwon.ac.kr.
  • 10 KW-Bio, Chuncheon, Republic of Korea. shhong@kangwon.ac.kr.
  • # Contributed equally.
PMID: 40887500 DOI: 10.1038/s12276-025-01524-y
Abstract

Normal mitochondrial function is essential for human induced pluripotent stem (hiPS) cell differentiation into definitive endoderm (DE). However, the underlying mechanisms that maintain mitochondrial homeostasis during DE differentiation are not fully elucidated. Here we report that glyoxalase 1 (GLO1) is a novel regulator of DE differentiation and subsequent alveolar development in hiPS cells via maintaining mitochondrial homeostasis. To determine the role of GLO1 in these processes, we first established GLO1-knockout hiPS cells using CRISPR-Cas9-mediated genome deletion and demonstrated that GLO1 deficiency significantly reduced the differentiation efficiency of DE, leading to defects in alveolar epithelial cell differentiation and alveolar Organoid development. Moreover, GLO1 deficiency interfered with mitochondrial biogenesis and respiration during the early DE stage. Defects in DE differentiation due to dysfunctional mitochondria were effectively rescued by high-dose treatment with CHIR99021, a glycogen synthase kinase 3 inhibitor. Our study uncovered an essential role of GLO1 as a key regulator of mitochondrial homeostasis for early lineage specification of hiPS cells, moving away from its conventional role as a primary enzyme in methylglyoxal detoxification.

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