Mitochondria are double membrane organelles in eukaryotic cells that provide energy by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They are crucial to many aspects of cellular metabolism. Mitochondria contain their own DNA that encodes for essential proteins involved in the execution of normal mitochondrial functions. Compared with nuclear DNA, the mitochondrial DNA (mtDNA) is more prone to be affected by DNA damaging agents, and accumulated DNA damages may cause mitochondrial dysfunction and drive the pathogenesis of a variety of human diseases, including neurodegenerative disorders and cancer. Therefore, understanding better how mtDNA damages are repaired will facilitate developing therapeutic strategies. In this review, we focus on our current understanding of the mtDNA repair system. We also discuss other mitochondrial events promoted by excessive DNA damages and inefficient DNA repair, such as mitochondrial fusion, fission, and mitophagy, which serve as quality control events for clearing damaged mtDNA.
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Primary liver cancer (PLC) is one of the most common types of cancer worldwide. Hepatocellular carcinoma (HCC) accounts for approximately 90% of PLC cases. The HCC microenvironment plays an important role in the occurrence and development of HCC. Immunotherapy for the HCC microenvironment has become an effective treatment strategy. T lymphocytes are an important part of the HCC microenvironment, and programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are the main immunosuppressive molecules of T lymphocytes. Transforming growth factor β1 (TGF-β1) can inhibit the immune function of T lymphocytes and promote the occurrence and development of tumors. However, few studies have explored whether TGF-β1 can upregulate the expression of PD-1 and CTLA-4 on T cells. In this study, we showed that TGF-β1 upregulated the expression of PD-1 and CTLA-4 on T lymphocytes and attenuated the cytotoxicity of T lymphocytes for HCC cells in vitro and in vivo. In addition, TGF-β1 increased the apoptosis of T lymphocytes induced by HCC cells. Finally, we found that the mechanism by which TGF-β1 upregulates the expression of PD-1 and CTLA-4 on T lymphocytes may be related to the calcineurin-nuclear factor of activated T cells 1 (CaN/NFATc1) pathway. This study will provide some experimental basis for liver cancer immunotherapy based on the tumor microenvironment.
Type 2 diabetes (T2D) is a complicated systemic disease, and the exact pathogenetic molecular mechanism is unclear. Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in diabetes. In the current study, C57BL/6 J mice were used to build T2D model, then treated with exendin-4 (10 μg/kg). Histone H3K9 and H3K23 acetylation, H3K4 monomethylation and H3K9 dimethylation were explored by Western blotting of liver histone extracts. Real-time polymerase chain reaction (PCR) was used to examine expression levels of diabetes-related genes, while chromatin immunoprecipitation (ChIP) was applied to analyze H3 and H3K9 acetylation, H3K4 monomethylation, and H3K9 dimethylation in the promoter of facilitated glucose transporter member 2 (Glut2) gene. The results showed that liver's total H3K4 monomethylation and H3K9 dimethylation was increased in diabetic mice, which was abrogated with the treatment of exendin-4. In contrast, H3K9 and H3K23 acetylation were reduced in diabetic mice, while exendin-4 only alleviated the reduction of H3K9 acetylation. Our data indicated that the progression of type 2 diabetes mellitus (T2D) is associated with global liver histone H3K9 and H3K23 acetylation, H3K4 monomethylation, and H3K9 dimethylation. Exploiting exact histone modify enzyme inhibitors, which may represent a novel strategy to prevent T2D.
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