A Mitochondrial DNA Variant Elevates the Risk of Gallstone Disease by Altering Mitochondrial Function

Dayan Sun; Zhenmin Niu; Hong-Xiang Zheng; Fei Wu; Liuyiqi Jiang; Tian-Quan Han; Yang Wei; Jiucun Wang; Li Jin

doi:10.1016/j.jcmgh.2020.11.015

A Mitochondrial DNA Variant Elevates the Risk of Gallstone Disease by Altering Mitochondrial Function

Cell Mol Gastroenterol Hepatol. 2021;11(4):1211-1226.e15. doi: 10.1016/j.jcmgh.2020.11.015. Epub 2020 Dec 4.

Authors

Dayan Sun¹, Zhenmin Niu², Hong-Xiang Zheng³, Fei Wu⁴, Liuyiqi Jiang⁴, Tian-Quan Han⁵, Yang Wei⁴, Jiucun Wang⁶, Li Jin⁷

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China.
² Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai, China.
³ Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China; Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China.
⁴ State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China.
⁵ Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁶ State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China; Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, China; Taizhou Institute of Health Sciences, Fudan University, Taizhou, China. Electronic address: jcwang@fudan.edu.cn.
⁷ State Key Laboratory of Genetic Engineering, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China; Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, China; Taizhou Institute of Health Sciences, Fudan University, Taizhou, China. Electronic address: lijin@fudan.edu.cn.

Abstract

Background and aims: Gallstone disease (cholelithiasis) is a cholesterol-related metabolic disorders with strong familial predisposition. Mitochondrial DNA (mtDNA) variants accumulated during human evolution are associated with some metabolic disorders related to modified mitochondrial function. The mechanistic links between mtDNA variants and gallstone formation need further exploration.

Methods: In this study, we explored the possible associations of mtDNA variants with gallstone disease by comparing 104 probands and 300 controls in a Chinese population. We constructed corresponding cybrids using trans-mitochondrial technology to investigate the underlying mechanisms of these associations. Mitochondrial respiratory chain complex activity and function and cholesterol metabolism were assessed in the trans-mitochondrial cell models.

Results: Here, we found a significant association of mtDNA 827A>G with an increased risk of familial gallstone disease in a Chinese population (odds ratio [OR]: 4.5, 95% confidence interval [CI]: 2.1-9.4, P=1.2×10^-4). Compared with 827A cybrids (haplogroups B4a and B4c), 827G cybrids (haplogroups B4b and B4d) had impaired mitochondrial respiratory chain complex activity and function and activated JNK and AMPK signaling pathways. Additionally, the 827G cybrids showed disturbances in cholesterol transport and accelerated development of gallstones. Specifically, cholesterol transport through the transporter ABCG5/8 was increased via activation of the AMPK signaling pathway in 827G cybrids.

Conclusions: Our findings reveal that mtDNA 827A>G induces aberrant mitochondrial function and abnormal cholesterol transport, resulting in increased occurrence of gallstones. The results provide an important biological basis for the clinical diagnosis and prevention of gallstone disease in the future.

Keywords: Chinese Population; Cholesterol Transport; Gallstone Disease; Mitochondrial Function; mtDNA 827A>G.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Asian People / genetics*
Case-Control Studies
China / epidemiology
Cholesterol / metabolism
DNA, Mitochondrial / analysis
DNA, Mitochondrial / genetics*
Female
Gallstones / epidemiology
Gallstones / genetics
Gallstones / pathology*
Genetic Predisposition to Disease*
Humans
Male
Middle Aged
Mitochondria / genetics
Mitochondria / pathology*
Polymorphism, Single Nucleotide*
Risk Factors
Young Adult

Substances

DNA, Mitochondrial
Cholesterol