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Mitochondrial ROS attack DNA readily, generating a variety of DNA damages such as oxidized bases and strand breaks. The major mechanism that cells use to repair oxidized bases such as 8-hydroxyguanine, formamidopyrimidine and 5-hydroxyuracil is base excision repair (BER). [14] BER occurs in both the cell nucleus and in mitochondria.
As the production of reactive oxygen species by these proton-pumping complexes is greatest at high membrane potentials, it has been proposed that mitochondria regulate their activity to maintain the membrane potential within a narrow range that balances ATP production against oxidant generation. [86]
If too much damage is present in mitochondria, a cell undergoes apoptosis or programmed cell death. [26] [27] In addition, ROS are produced in immune cell signaling via the NOX pathway. Phagocytic cells such as neutrophils, eosinophils, and mononuclear phagocytes produce ROS when stimulated. [28] [29]
During ATP production electrons can escape the mitochondrion and react with water, producing reactive oxygen species, ROS for short. ROS can damage macromolecules, including lipids, proteins and DNA, which is thought to facilitate the process of ageing. Electron transport chain in the inner mitochondrial membrane
Illustration of the malate–aspartate shuttle pathway. The malate–aspartate shuttle (sometimes simply the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryotes.
These radicals then damage the mitochondria's DNA and proteins, and these damage components in turn are more liable to produce ROS byproducts. Thus a positive feedback loop of oxidative stress is established that, over time, can lead to the deterioration of cells and later organs and the entire body. [26]
Mitochondrial matrix has a pH of about 7.8, which is higher than the pH of the intermembrane space of the mitochondria, which is around 7.0–7.4. [5] Mitochondrial DNA was discovered by Nash and Margit in 1963. One to many double stranded mainly circular DNA is present in mitochondrial matrix. Mitochondrial DNA is 1% of total DNA of a cell.
The mitochondrial unfolded protein response (UPR mt) is a cellular stress response related to the mitochondria. The UPR mt results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them. [1] The UPR mt can occur either in the mitochondrial matrix or in the mitochondrial inner membrane. [1]