Mitochondrial Signaling Pathways Associated with DNA Damage Responses

Abstract

Under physiological and stress conditions, mitochondria act as a signaling platform to initiate biological events, establishing communication from the mitochondria to the rest of the cell. Mitochondrial adenosine triphosphate (ATP), reactive oxygen species, cytochrome C, and damage-associated molecular patterns act as messengers in metabolism, oxidative stress response, bystander response, apoptosis, cellular senescence, and inflammation response. In this review paper, the mitochondrial signaling in response to DNA damage was summarized. Mitochondrial clearance via fusion, fission, and mitophagy regulates mitochondrial quality control under oxidative stress conditions. On the other hand, damaged mitochondria release their contents into the cytoplasm and then mediate various signaling pathways. The role of mitochondrial dysfunction in radiation carcinogenesis was discussed, and the recent findings on radiation-induced mitochondrial signaling and radioprotective agents that targeted mitochondria were presented. The analysis of the mitochondrial radiation effect, as hypothesized, is critical in assessing radiation risks to human health.

Quercetin Alleviates Toxicity Induced by High Levels of Copper in Porcine Follicular Granulosa Cells by Scavenging Reactive Oxygen Species and Improving Mitochondrial Function

“…Alterations in mitochondrial morphology and function are associated with the cytotoxicity of copper. Damaged mitochondria not only fail to produce energy efficiently, but also excessively accumulate ROS [52], leading to Ca 2+ imbalance, which may exacerbate cell damage caused by high copper. We examined the mtROS content in our experiments, and as expected, the mtROS level increased with the increase in high CuSO 4 concentration (≥200 µM).…”

DAMPs and radiation injury

“…These cells are unable to complete the cell cycle, ultimately leading to their entry into senescence or their demise through apoptosis or necrosis ( 27 ). Exposure to ionizing radiation can affect not only nuclear DNA, but also other cellular organelles including mitochondria, Golgi apparatus, and lysosomes ( 29 ). Mitochondria serve as the primary generators of ROS within the cells.…”

“…Mitochondria serve as the primary generators of ROS within the cells. Radiation-induced mitochondrial DNA damage induces ROS generation, leading to a decrease in mitochondrial membrane potential and inducing mitochondria outer membrane permeabilization (MOMP) ( 29 ). The subsequent release of cytochrome c and activation of caspase-9 lead to apoptosis ( 30 ).…”

“…mtDNA is susceptible to ionizing radiation compared to nuclear DNA due to the lack of protective histones and limited repair mechanism ( 29 ). Mitochondrial dysfunction resulting from failure of DNA repair leads to the release of mitochondrial components including cytochrome c, ATP, mtDNA, and mtRNA ( 29 ).…”

“…mtDNA is susceptible to ionizing radiation compared to nuclear DNA due to the lack of protective histones and limited repair mechanism ( 29 ). Mitochondrial dysfunction resulting from failure of DNA repair leads to the release of mitochondrial components including cytochrome c, ATP, mtDNA, and mtRNA ( 29 ). The mtDNA in the cytosol is recognized by the cyclic GMP-AMP synthase (cGAS) to activate the stimulator of interferon genes (STING) signaling pathway, resulting in the production of type I interferons (IFNs) ( 65 , 70 ).…”