Mitochondrial theory of ageing
The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978. The mitochondrial free radical theory of ageing (MFRTA) proposes that free radicals produced by mitochondrial activity damage cellular components, leading to ageing. Mitochondria are cell organelles which function to provide the cell with energy by producing ATP (adenosine triphosphate). 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. In the 1950s Denham Harman proposed the free radical theory of ageing, which he later expanded to the MFRTA. When studying the mutations in antioxidants, which remove ROS, results were inconsistent. However, it has been observed that overexpression of antioxidant enzymes in yeast, worms, flies and mice were shown to increase lifespan. Molecular basis Mitochondria are thought to be organelles that developed from endocytosed bacteria which learned to coexist inside ancient cells. These bacteria maintained their own DNA, the mitochondrial DNA (mtDNA), which codes for components of the electron transport chain (ETC). The ETC is found in the inner mitochondrial membrane and functions to produce energy in the form of ATP molecules. The process is called oxidative phosphorylation, because ATP is produced from ADP in a series of redox reactions. Electrons are transferred through the ETC from NADH and FADH2 to oxygen, reducing oxygen to water. ROS ROS are highly reactive, oxygen-containing chemical species, which include superoxide, hydrogen peroxide and hydroxyl radical. If the complexes of the ETC do not function properly, electrons can leak and react with water, forming ROS. Normally leakage is low and ROS is kept at physiological levels, fulfilling roles in signaling and homeostasis. In fact, their presence at low levels lead to increased life span, by activating transcription factors and metabolic pathways involved in longevity. At increased levels ROS cause oxidative damage by oxidizing macromolecules, such as lipids, proteins and DNA. This oxidative damage to macromolecules is thought to be the cause of ageing. Mitochondrial DNA is especially susceptible to oxidative damage, due to its proximity to the site of production of these species. Damaging of mitochondrial DNA causes mutations, leading to production of ETC complexes, which don’t function properly, increasing ROS production, increasing oxidative damage to macromolecules. UPRmt The mitochondrial unfolded protein response (UPRmt) is turned on in response to mitochondrial stress. Mitochondrial stress occurs when the proton gradient across the inner mitochondrial membrane is dissipated, mtDNA is mutated, and/or ROS accumulates, which can lead to misfolding and reduced function of mitochondrial proteins. Stress is sensed by the nucleus, where chaperones and proteases are upregulated, which can correct folding or remove damaged proteins, respectively. Decrease in protease levels are associated