Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with poor prognosis due to its high metastatic potential, however, the role of metabolic reprogramming in the metastasis of PDAC cell is not known. Here, we report that COX6B2 drive metastasis but not cancer cell proliferation in PDAC by enhancing oxidative phosphorylation function (OXPHOS). Transcriptome and clinical analyses revealed that cytochrome c oxidase subunit 6B2 (COX6B2) positively associated with metastasis of PDAC cells. Knockdown of COX6B2 in PDAC cells tuned down the assembly of complex IV and downregulated the function of OXPHOS, whereas re-expression of COX6B2 restored the function of OXPHOS and metastatic potential. Mechanistically, COX6B2 upregulated OXPHOS function to active purinergic receptor pathway for the metastasis of PDAC cells. Notably, the metastatic potential in PDAC could be reversely regulated by metformin, a drug was found accelerating the degradation of COX6B2 mRNA in this study. Collectively, our findings indicated that a complex metabolic control mechanism might be involved in achieving the balance of metabolic requirements for both growth and metastasis in PDAC, and regulation of the expression of COX6B2 could potentially encompass one of the targets.

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.

Mitochondrial dysfunction is closely associated with the pathogenesis of nonalcoholic steatohepatitis (NASH). The aim of the present study was to comprehensively determine mitochondrial abnormalities in NASH by detecting the proteomics in liver mitochondria in a NASH rat model, which was induced for 16 weeks by the provision of a high fat and high cholesterol diet (HFD). Serum parameters, including triglycerides, total cholesterol, low‑density lipoprotein cholesterol and high‑density lipoprotein cholesterol were determined, and hematoxylin and eosin staining of liver tissues was examined to evaluate the NASH rat model. Various parameters associated with mitochondrial function were examined, including mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential (MMP) and mitochondrial respiratory chain complex (MRC) activity. The mitochondrial proteomics were analyzed and identified using isobaric tags for relative and absolute quantitation labeling coupled with two‑dimensional liquid chromatography‑tandem mass spectrometry. The identified proteins were classified and grouped using the Blast2GO program against the non‑redundant protein database, the Kyoto Encyclopedia of Genes and Genomes database and the Cluster of Orthologous Groups of proteins database. Compared with the control, mtDNA copy number, MMP, and activities of MRC I and III were decreased markedly in the HFD group. A total of 18 upregulated and 13 downregulated proteins were identified, with a significant 1.2‑fold difference between the control and NASH groups. The dysregulated proteins were closely involved in mitochondrial oxidative phosphorylation, the lipid metabolic process and fatty acid β‑oxidation. The results of the present study provide important proteomic information regarding liver mitochondria in NASH and serve as a basis for further detailed investigations of the pathogenesis of NASH.