Abstract
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.
Highlights
Mammalian mitochondria contain an independent genome referred to as mitochondrial DNA that comprises16,569 nucleotide pairs encoding 13 essential polypeptides of the respiratory chain complex, as well as two rRNAs and 22 tRNAs necessary for gene expression [1]
G3842A is a nonsense mutation in nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase (ND) subunit 1 gene (ND1), which encodes a part of complex I. We previously identified this mutation in papillary thyroid carcinoma [18], and it has been identified in follicular thyroid carcinoma (FTC) [15] and liver cancer [19], suggesting the pathogenicity of G3842A
We found that the genes with the highest frequency of mitochondrial DNA (mtDNA) mutations were ND4 and cytochrome c oxidase subunit 1 (CO1), followed by NADH dehydrogenase subunit 1 gene (ND1) and cytochrome b (CYB) (Figure 1(a)), with the majority of mtDNA mutations occurring in complex I (Figure 1(b))
Summary
Mammalian mitochondria contain an independent genome referred to as mitochondrial DNA (mtDNA) that comprises16,569 nucleotide pairs encoding 13 essential polypeptides of the respiratory chain complex, as well as two rRNAs and 22 tRNAs necessary for gene expression [1]. Oxidative Medicine and Cellular Longevity damage and has a higher mutation rate because of its proximity to reactive oxygen species (ROS) produced by the respiratory chain, lack of histone proteins, and limited DNA repair activity [2] [3]. Somatic mutations in mtDNA are frequently detected in cancerous tissues, including liver [4], breast [5], colorectal [6], prostate [7], and thyroid [8] cancers, few functional studies of these mutations have been described. It remains a matter of debate as to whether mtDNA mutations represent oncogenic events or byproducts of tumorigenesis. The BRAF V600E mutation leads to continuous activation of the MAPK pathway to promote oncogenic transformation [12]. It is generally believed that the incidence of thyroid cancer is related to inherited genetic syndromes, radiation exposure, and hormone and iodine deficiencies [13]
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