Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies.

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

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Peripheral blood mitochondrial DNA copy number as a predictor of steatotic liver disease development: insights from epidemiological and experimental studies.

Author: Genki MIZUNO ¹ ; Atsushi TESHIGAWARA ² ; Hiroya YAMADA ³ ; Eiji MUNETSUNA ⁴ ; Yoshiki TSUBOI ² ; Yuji HATTORI ² ; Mirai YAMAZAKI ³ ; Yoshitaka ANDO ⁵ ; Itsuki KAGEYAMA ² ; Takuya WAKASUGI ³ ; Naohiro ICHINO ⁶ ; Keisuke OSAKABE ⁶ ; Keiko SUGIMOTO ⁶ ; Ryosuke FUJII ² ; Hiroaki ISHIKAWA ⁵ ; Nobutaka OHGAMI ³ ; Koji OHASHI ⁵ ; Koji SUZUKI ²
Author Information

1. Department of Medical Technology, Tokyo University of Technology School of Health Sciences.
2. Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences.
3. Department of Hygiene, Fujita Health University School of Medicine.
4. Department of Animal Science and Biotechnology, Azabu University School of Veterinary Medicine.
5. Department of Informative Clinical Medicine, Fujita Health University School of Medical Sciences.
6. Department of Clinical Physiology, Fujita Health University School of Medical Sciences.
Publication Type:Journal Article
Keywords: Mitochondria; Mitochondrial DNA-copy number; Peripheral blood; Predictive marker; Steatotic liver disease
MeSH: Animals; DNA, Mitochondrial/genetics*; Humans; Male; DNA Copy Number Variations; Female; Fatty Liver/blood*; Rats; Middle Aged; Longitudinal Studies; Rats, Sprague-Dawley; Adult; Japan/epidemiology*; Aged; Biomarkers/blood*; Hep G2 Cells; Diet, High-Fat/adverse effects*
From:Environmental Health and Preventive Medicine 2025;30():42-42
CountryJapan
Language:English
Abstract: 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.