Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies
Background: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabo...
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Komiyama Printing Co. Ltd
2025-05-01
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| Series: | Environmental Health and Preventive Medicine |
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| author | Genki Mizuno Atsushi Teshigawara Hiroya Yamada Eiji Munetsuna Yoshiki Tsuboi Yuji Hattori Mirai Yamazaki Yoshitaka Ando Itsuki Kageyama Takuya Wakasugi Naohiro Ichino Keisuke Osakabe Keiko Sugimoto Ryosuke Fujii Hiroaki Ishikawa Nobutaka Ohgami Koji Ohashi Koji Suzuki |
| author_facet | Genki Mizuno Atsushi Teshigawara Hiroya Yamada Eiji Munetsuna Yoshiki Tsuboi Yuji Hattori Mirai Yamazaki Yoshitaka Ando Itsuki Kageyama Takuya Wakasugi Naohiro Ichino Keisuke Osakabe Keiko Sugimoto Ryosuke Fujii Hiroaki Ishikawa Nobutaka Ohgami Koji Ohashi Koji Suzuki |
| author_sort | Genki Mizuno |
| collection | DOAJ |
| description | Background: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). Methods: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. Results: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08–22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. Conclusions: Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment. |
| format | Article |
| id | doaj-art-2a42a5d5121141c5b25ff0656cb0f231 |
| institution | DOAJ |
| issn | 1342-078X 1347-4715 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Komiyama Printing Co. Ltd |
| record_format | Article |
| series | Environmental Health and Preventive Medicine |
| spelling | doaj-art-2a42a5d5121141c5b25ff0656cb0f2312025-08-20T03:21:50ZengKomiyama Printing Co. LtdEnvironmental Health and Preventive Medicine1342-078X1347-47152025-05-0130424210.1265/ehpm.25-00025ehpmPeripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studiesGenki Mizuno0Atsushi Teshigawara1Hiroya Yamada2Eiji Munetsuna3Yoshiki Tsuboi4Yuji Hattori5Mirai Yamazaki6Yoshitaka Ando7Itsuki Kageyama8Takuya Wakasugi9Naohiro Ichino10Keisuke Osakabe11Keiko Sugimoto12Ryosuke Fujii13Hiroaki Ishikawa14Nobutaka Ohgami15Koji Ohashi16Koji Suzuki17Department of Medical Technology, Tokyo University of Technology School of Health SciencesDepartment of Preventive Medical Sciences, Fujita Health University School of Medical SciencesDepartment of Hygiene, Fujita Health University School of MedicineDepartment of Animal Science and Biotechnology, Azabu University School of Veterinary MedicineDepartment of Preventive Medical Sciences, Fujita Health University School of Medical SciencesDepartment of Preventive Medical Sciences, Fujita Health University School of Medical SciencesDepartment of Hygiene, Fujita Health University School of MedicineDepartment of Informative Clinical Medicine, Fujita Health University School of Medical SciencesDepartment of Preventive Medical Sciences, Fujita Health University School of Medical SciencesDepartment of Hygiene, Fujita Health University School of MedicineDepartment of Clinical Physiology, Fujita Health University School of Medical SciencesDepartment of Clinical Physiology, Fujita Health University School of Medical SciencesDepartment of Clinical Physiology, Fujita Health University School of Medical SciencesDepartment of Preventive Medical Sciences, Fujita Health University School of Medical SciencesDepartment of Informative Clinical Medicine, Fujita Health University School of Medical SciencesDepartment of Hygiene, Fujita Health University School of MedicineDepartment of Informative Clinical Medicine, Fujita Health University School of Medical SciencesDepartment of Preventive Medical Sciences, Fujita Health University School of Medical SciencesBackground: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). Methods: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. Results: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08–22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. Conclusions: Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.https://www.jstage.jst.go.jp/article/ehpm/30/0/30_25-00025/_html/-char/enmitochondriamitochondrial dna-copy numbersteatotic liver diseaseperipheral bloodpredictive marker |
| spellingShingle | Genki Mizuno Atsushi Teshigawara Hiroya Yamada Eiji Munetsuna Yoshiki Tsuboi Yuji Hattori Mirai Yamazaki Yoshitaka Ando Itsuki Kageyama Takuya Wakasugi Naohiro Ichino Keisuke Osakabe Keiko Sugimoto Ryosuke Fujii Hiroaki Ishikawa Nobutaka Ohgami Koji Ohashi Koji Suzuki Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies Environmental Health and Preventive Medicine mitochondria mitochondrial dna-copy number steatotic liver disease peripheral blood predictive marker |
| title | Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies |
| title_full | Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies |
| title_fullStr | Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies |
| title_full_unstemmed | Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies |
| title_short | Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies |
| title_sort | peripheral blood mitochondrial dna copy number as a predictor of steatotic liver disease development insights from epidemiological and experimental studies |
| topic | mitochondria mitochondrial dna-copy number steatotic liver disease peripheral blood predictive marker |
| url | https://www.jstage.jst.go.jp/article/ehpm/30/0/30_25-00025/_html/-char/en |
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