Our current understanding of the biological impact of endometrial cancer mtDNA genome mutations and their potential use as a biomarker

Endometrial cancer (EC) is a devastating and common disease affecting women’s health. The NCI Surveillance, Epidemiology, and End Results Program predicted that there would be >66,000 new cases in the United States and >13,000 deaths from EC in 2023, and EC is the sixth most common cancer among women worldwide. Regulation of mitochondrial metabolism plays a role in tumorigenesis. In proliferating cancer cells, mitochondria provide the necessary building blocks for biosynthesis of amino acids, lipids, nucleotides, and glucose. One mechanism causing altered mitochondrial activity is mitochondrial DNA (mtDNA) mutation. The polyploid human mtDNA genome is a circular double-stranded molecule essential to vertebrate life that harbors genes critical for oxidative phosphorylation plus mitochondrial-derived peptide genes. Cancer cells display aerobic glycolysis, known as the Warburg effect, which arises from the needs of fast-dividing cells and is characterized by increased glucose uptake and conversion of glucose to lactate. Solid tumors often contain at least one mtDNA substitution. Furthermore, it is common for cancer cells to harbor mixtures of wild-type and mutant mtDNA genotypes, known as heteroplasmy. Considering the increase in cancer cell energy demand, the presence of functionally relevant carcinogenesis-inducing or environment-adapting mtDNA mutations in cancer seems plausible. We review 279 EC tumor-specific mtDNA single nucleotide variants from 111 individuals from different studies. Many transition mutations indicative of error-prone DNA polymerase γ replication and C to U deamination events were present. We examine the spectrum of mutations and their heteroplasmy and discuss the potential biological impact of recurrent, non-synonymous, insertion, and deletion mutations. Lastly, we explore current EC treatments, exploiting cancer cell mitochondria for therapy and the prospect of using mtDNA variants as an EC biomarker

From the mountains to the plains: impact of climate change on water resources in the Koshi River Basin

The Koshi Basin, spread across China, Nepal and India, is perceived as having high potential for hydropower and irrigation development, both seen as ways to promote economic development in the region. This paper quantifies and assesses the past and projected future spatial and temporal water balances in the Koshi Basin. Results show that precipitation and net water yield are lowest in the transmountain region and the Tibetan plateau. The values are highest in the mountain region, followed by the hills and Indo-Gangetic Plains. Approximately 65% of average annual precipitation is converted to flows, indicating high water availability. Actual evapotranspiration is highest in the Indo-Gangetic Plains region due to the presence of irrigated agriculture and a few forested mountain watersheds. As most of the water from the mountain and hill regions eventually flows down to the plains, the mountain and hill regions in Nepal are important for maintaining agriculture in the plains in both Nepal and India. Results from the flow analyses indicate the high temporal variability of flows in the basin. The frequent occurrences of both high- and low-flow events demonstrate the existing vulnerability of the region to both floods and droughts, leading to a very risk-prone livelihood system. Climate change projections show an increasing trend in precipitation and net water yield for most of the basin, except the transmountain region. Therefore, it is important to consider the climate change impacts on water resources in future planning

Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation