Dr. Hideaki Matsui, Professor, Department of Neuroscience of Disease, Brain Research Institute, Niigata University2021.11 ～ 2023.11― 269 ―The aging process can compromise the integrity of a cell’s nuclear membrane, leading to the leakage of nuclear DNA into the cytosol and activation of the cGAS-STING pathway, contributing to various aging-related phenotypes. Although extensive research has focused on nuclear DNA leakage, the release of mitochondrial DNA (mtDNA) into the cytosol, with potentially more harmful effects, has been relatively understudied. Our laboratory has a strong history of investigating aging-related processes using diverse models and human samples. The presence of ectopic DNA in the cytoplasm triggers inflammation and cell death, primarily detected by cyclic GMP-AMP synthase (cGAS) in the case of nuclear DNA leakage. Our recent studies have revealed that cytoplasmic double-stranded DNA (dsDNA) of mitochondrial origin, resistant to lysosomal degradation, induces significant cytotoxicity both in cultured cells and in vivo 1). Cytoplasmic mitochondrial DNA is increasingly recognized as a factor in various diseases, yet current methods for assessing it in the cytoplasm may lack precision. Therefore, we introduce a detailed method for evaluating ectopic mitochondrial DNA within cells, offering valuable insights for basic research and investigations into aging, Parkinson’s disease, Alzheimer’s disease, heart failure, autoimmune diseases, cancer, and other conditions 2). Mitochondria are pivotal in cellular metabolism and stability maintenance. When mtDNA is released into the cytoplasm due to compromised mitochondrial function triggered by infections, diseases, or environmental stressors, it can initiate inflammation and cell death. Cytoplasmic mtDNA has implications in diseases like Parkinson’s disease, Alzheimer’s disease, and cancer. Despite numerous DNA sensor proteins identified, their specific functions and a comprehensive sensor list remain unclear. This study aims to explore whether DDX41, a member of the DEAD/DEAH-box RNA helicase family known for detecting cytoplasmic viral DNA, can also recognize leaked mtDNA, potentially triggering inflammation.The hypothalamic-pituitary-adrenal (HPA) axis is crucial for regulating responses to stress, with dysregulation linked to various stress-related diseases, especially with aging. Typically, stress prompts the hypothalamus to release corticotropin-releasing hormone (CRH), stimulating the pituitary gland to release adrenocorticotropic hormone (ACTH). This, in turn, triggers the adrenal gland to release glucocorticoids (GCs), such as cortisol in humans. GCs help combat stress throughout the body, including the brain, and maintain IntroductionThe differential roles of various DNA sensors in human age-related diseasesMohammad Tufazzal Hussan
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