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

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.

Association of m.5178C>A variant with serum lipid levels: a systematic review and meta-analysis

“…Together, it indicated that the damage of mtDNA was associated with dyslipidemia. Notably, this speculation was verified by Sun et al [ 11 ]. Moreover, an emerging study [ 12 ] reported that m.5178C>A variant was associated with improved mitochondrial functions.…”

Adeno-Associated Virus based Caveolin-1 Delivery via Different Routes for the Prevention of Cholesterol Gallstone Formation

“…According to a large epidemiological work, AMPK may positively affect CGD via the transactivation of ABCG5/G8 [22]. And animal studies have shown that ABCG5/G8 plays a direct role in the process that leads to bile cholesterol supersaturation, which reduces hepatic cholesterol burden [23].…”

The Mitochondrial tRNAPhe 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis

“…Here, these mitochondrial genomes of A6, A7, and A40 pedigrees belong to the Eastern Asian haplogroups H2, F4b, and M10a, respectively. In the other studies, two Chinese cholecystolithiasis pedigrees carrying the m.827A > G belonged to the haplogroups B4a and B4c ( Sun et al, 2021 ). This implied that the m.625G > A mutation, similar to other mitochondrial mutations, occurred sporadically and multiplied through the evolution of the mtDNA ( Liang et al, 2014 ).…”