Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency
Abstract Somatic cell reprogramming into human induced pluripotent stem cells entails significant intracellular changes, including modifications in mitochondrial metabolism and a decrease in mitochondrial DNA copy number. However, the mechanisms underlying this decrease in mitochondrial DNA copy num...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01476-3 |
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| author | Hyun Kyu Kim Yena Song Minji Kye Byeongho Yu Hyung Kyu Choi Sung-Hwan Moon Man Ryul Lee |
| author_facet | Hyun Kyu Kim Yena Song Minji Kye Byeongho Yu Hyung Kyu Choi Sung-Hwan Moon Man Ryul Lee |
| author_sort | Hyun Kyu Kim |
| collection | DOAJ |
| description | Abstract Somatic cell reprogramming into human induced pluripotent stem cells entails significant intracellular changes, including modifications in mitochondrial metabolism and a decrease in mitochondrial DNA copy number. However, the mechanisms underlying this decrease in mitochondrial DNA copy number during reprogramming remain unclear. Here we aimed to elucidate these underlying mechanisms. Through a meta-analysis of several RNA sequencing datasets, we identified genes responsible for the decrease in mitochondrial DNA. We investigated the functions of these identified genes and assessed their regulatory mechanisms. In particular, the expression of the thymidine kinase 2 gene (TK2), located in the mitochondria and required for mitochondrial DNA synthesis, is decreased in human pluripotent stem cells as compared with its expression in somatic cells. TK2 was significantly downregulated during reprogramming and markedly upregulated during differentiation. Collectively, this decrease in TK2 levels induces a decrease in mitochondrial DNA copy number and contributes to shaping the metabolic characteristics of human pluripotent stem cells. However, contrary to our expectations, treatment with a TK2 inhibitor impaired somatic cell reprogramming. These results suggest that decreased TK2 expression may result from metabolic conversion during somatic cell reprogramming. |
| format | Article |
| id | doaj-art-e5e23873d6574d35b183e7ad2bd4aa72 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-e5e23873d6574d35b183e7ad2bd4aa722025-08-20T04:01:47ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-06-015761272128210.1038/s12276-025-01476-3Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotencyHyun Kyu Kim0Yena Song1Minji Kye2Byeongho Yu3Hyung Kyu Choi4Sung-Hwan Moon5Man Ryul Lee6Soonchunhyang Institute of Medi-bio Science, Soon Chun Hyang UniversitySoonchunhyang Institute of Medi-bio Science, Soon Chun Hyang UniversitySoonchunhyang Institute of Medi-bio Science, Soon Chun Hyang UniversitySoonchunhyang Institute of Medi-bio Science, Soon Chun Hyang UniversityDepartment of Animal Science and Technology, Chung-Ang UniversityDepartment of Animal Science and Technology, Chung-Ang UniversityDepartment of Stem Cell and Regenerative Biotechnology, KU Institute of Science and Technology, The Institute of Advanced Regenerative Science, Konkuk UniversityAbstract Somatic cell reprogramming into human induced pluripotent stem cells entails significant intracellular changes, including modifications in mitochondrial metabolism and a decrease in mitochondrial DNA copy number. However, the mechanisms underlying this decrease in mitochondrial DNA copy number during reprogramming remain unclear. Here we aimed to elucidate these underlying mechanisms. Through a meta-analysis of several RNA sequencing datasets, we identified genes responsible for the decrease in mitochondrial DNA. We investigated the functions of these identified genes and assessed their regulatory mechanisms. In particular, the expression of the thymidine kinase 2 gene (TK2), located in the mitochondria and required for mitochondrial DNA synthesis, is decreased in human pluripotent stem cells as compared with its expression in somatic cells. TK2 was significantly downregulated during reprogramming and markedly upregulated during differentiation. Collectively, this decrease in TK2 levels induces a decrease in mitochondrial DNA copy number and contributes to shaping the metabolic characteristics of human pluripotent stem cells. However, contrary to our expectations, treatment with a TK2 inhibitor impaired somatic cell reprogramming. These results suggest that decreased TK2 expression may result from metabolic conversion during somatic cell reprogramming.https://doi.org/10.1038/s12276-025-01476-3 |
| spellingShingle | Hyun Kyu Kim Yena Song Minji Kye Byeongho Yu Hyung Kyu Choi Sung-Hwan Moon Man Ryul Lee Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency Experimental and Molecular Medicine |
| title | Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency |
| title_full | Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency |
| title_fullStr | Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency |
| title_full_unstemmed | Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency |
| title_short | Changes in mitochondrial thymidine metabolism and mtDNA copy number during induced pluripotency |
| title_sort | changes in mitochondrial thymidine metabolism and mtdna copy number during induced pluripotency |
| url | https://doi.org/10.1038/s12276-025-01476-3 |
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