Journal Article

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

Han, Seon-Sook, Rasaei, Roya, Hong, Seok-Ho, Jeong, Suji, Hong, In Sun, Kim, Woo Jin, Kang, Minje, Yang, Se-Ran, Kim, Ji-Young, Koh, Hyebin, Lee, Jong-Hee

2025

Overview

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. Mitochondrial function linked to GLO1 in stem cells The study explores how a protein called glyoxalase 1 (GLO1) affects the development of lung cells from human induced pluripotent stem (hiPS) cells. Researchers found that GLO1 is crucial for the proper formation of definitive endoderm (DE). They used CRISPR–Cas9, a gene-editing tool, to create hiPS cells without GLO1 and observed that these cells struggled to develop into DE and lung cells. This was linked to problems with mitochondria, the cell’s energy producers. The team tested if a chemical called CHIR99021 could fix these issues. CHIR99021 is known to help cells develop by activating a pathway involving β-catenin, a protein important for cell growth. High doses of CHIR99021 improved mitochondrial function and helped the GLO1-deficient cells develop properly. The study concludes that GLO1 plays an essential role in early cell development by maintaining healthy mitochondria. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/100 / 13/31 / 14/63 / 45/41 / 631/532/1360 / 631/532/2064/2158 / 82/80 / Alveoli / Antibodies / Artificial intelligence / Biomedical and Life Sciences / Biomedicine / Cell culture / Cell Differentiation / CRISPR / Detoxification / Endoderm / Endoderm - cytology / Endoderm - metabolism / Epithelial cells / Flow cytometry / Genome editing / Glycogen / Glycogen synthase kinase 3 / Homeostasis / Humans / Induced Pluripotent Stem Cells - cytology / Induced Pluripotent Stem Cells - metabolism / Lactoylglutathione Lyase - deficiency / Lactoylglutathione Lyase - genetics / Lactoylglutathione Lyase - metabolism / Medical Biochemistry / Metabolism / Metabolites / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Molecular Medicine / Organoids / Pluripotency / Pluripotent Stem Cells - metabolism / Pyruvaldehyde / Software / Stem Cells / β-Catenin / 생화학