Mitochondrial DNA Haplogroup N9a Negatively Correlates with Incidence of Hepatocellular Carcinoma in Northern China

Hua, Shixuan; Li, Meinan; Zhao, Qiongya; Wang, Junyi; Zhou, Yaping; Liu, Jiangtao; Fang, Hezhi; Jiang, Minghua; Shen, Lijun

doi:10.1016/j.omtn.2019.09.001

Cited by 4 publications

(3 citation statements)

References 41 publications

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“…The 143B osteosarcoma ρ0 cell line was the first mtDNA-deleted cell model successfully constructed 35 and has been widely used to study human evolution-related topics, such as mtDNA haplogroup function in East Asia 36 and high-altitude population adaptability. 37 In addition, many diseases, including diabetes, 38 osteoarthritis, 39 and hepatocellular carcinoma, 40 have been studied in this cell model. Therefore, we chose the 143B osteosarcoma ρ0 cell line in combination with 827A- and 827G-related haplogroups plasma for our research.…”

Section: Discussionmentioning

confidence: 99%

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

Sun

Niu

Zheng

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Sun

Niu

Zheng

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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“…Transcriptome Sequencing and Analysis. Total RNA was extracted from cells with and without the G3842A mutation, and transcriptome sequencing was performed by Novogene (Nanjing, China), as previously described [24]. Gene expression was analyzed using DESeq2 R (https:// bioconductor.org/packages/release/bioc/html/DESeq2 .html), and an adjusted P < 0:05 was used to select differentially expressed genes (DEGs).…”

Section: Polymerase Chain Reaction-restriction Fragment Lengthmentioning

confidence: 99%

Thyroid Cancer-Associated Mitochondrial DNA Mutation G3842A Promotes Tumorigenicity via ROS-Mediated ERK1/2 Activation

Chen

Bao²,

Chen

et al. 2022

Oxidative Medicine and Cellular Longevity

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Mitochondrial DNA (mtDNA) mutations have been identified in various human cancers, including thyroid cancer. However, the relationship between mtDNA and thyroid cancer remains unclear. Previous studies by others and us strongly suggested that mtDNA mutations in complex I may participate in thyroid cancer processes according to sequencing results of thyroid cancer tissue, although the associated pathogenic processes remain unknown. Here, to investigate whether mtDNA mutations contribute to thyroid cancer, we reanalyzed our sequencing results and characterized thyroid cancer-associated mutations in the mitochondrial complex. The results identified the highest mutation frequencies in nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase subunit 4 gene (ND4) and cytochrome c oxidase subunit 1 gene (COI), which also harbored the highest rates of G > A substitutions, with most of the mutations resulting in changes in the polarity of amino acids. We then established cybrids containing the G3842A mutation identified in papillary thyroid carcinoma, which revealed it as a mutation in NADH dehydrogenase subunit 1 gene (ND1) and is previously reported in follicular thyroid carcinoma, thereby suggesting a possibly pathogenic role in thyroid carcinoma. Additionally, we found that the G3842A mutation accelerates tumorigenicity and decreases the abundance and activity of mitochondrial complex I, the oxygen consumption rate, and adenosine triphosphate levels. By contrast, the levels of reactive oxygen species (ROS) were increased to activate extracellular signal-regulated kinase (ERK1/2) signaling, which contributed to tumorigenicity. These findings suggest for the first time that mtDNA mutations help drive tumor development and that G3842A may represent a new risk factor for thyroid cancer. Furthermore, our findings indicate that drugs targeting ROS and ERK1/2 may serve as a viable therapeutic strategy for thyroid cancer.

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“…The mitochondrial retrograde signaling pathways of two N9a hybrids and three non-N9A hybrids were observed. The effect of this retrograde signaling change on diabetes in cellular models was further studied (Hua et al, 2019). The experiment revealed the mechanism of N9a in T2D and established the mitochondrial retrograde signaling pathway.…”

Section: Mtdna Copy Number Loss In Metabolic Syndromementioning

confidence: 97%

Mitochondrial DNA abnormalities and metabolic syndrome

Ding

Fang

Pang

et al. 2023

Front. Cell Dev. Biol.

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Metabolic syndrome (MetS) is a complex pathological condition that involves disrupted carbohydrate, protein, and fat metabolism in the human body, and is a major risk factor for several chronic diseases, including diabetes, cardiovascular disease, and cerebrovascular disease. While the exact pathogenesis of metabolic syndrome is not yet fully understood, there is increasing evidence linking mitochondrial dysfunction, which is closely related to the mitochondrial genome and mitochondrial dynamics, to the development of this condition. Recent advancements in genetic sequencing technologies have allowed for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with metabolic syndrome. Additionally, the identification of specific mechanisms by which reduced mtDNA copy number and gene mutations, as well as abnormalities in mtDNA-encoded proteins and mitochondrial dynamics, contribute to metabolic syndrome may promote the development of novel therapeutic targets and interventions, such as the restoration of mitochondrial function through the targeting of specific mitochondrial defects. Additionally, advancements in genetic sequencing technologies may allow for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with MetS. Therefore, strategies to promote the restoration of mitochondrial function by addressing these defects may offer new options for treating MetS. This review provides an overview of the research progress and significance of mitochondrial genome and mitochondrial dynamics in MetS.

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Mitochondrial DNA Haplogroup N9a Negatively Correlates with Incidence of Hepatocellular Carcinoma in Northern China

Cited by 4 publications

References 41 publications

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

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

Thyroid Cancer-Associated Mitochondrial DNA Mutation G3842A Promotes Tumorigenicity via ROS-Mediated ERK1/2 Activation

Mitochondrial DNA abnormalities and metabolic syndrome

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