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Mitochondrial Dysfunction

Mitochondrial dysfunction is the creation of dysfunction through the creation of reactive oxygen species (ROS), the effect of hormesis, and the decrease in biogenesis in mitochondria. This often affects oxidative phosphorylation and the amount of energy in the body.

The mitochondrion is an organelle inside of a eukaryotic cell. The mitochondrion has two ogranelle membranes. In these membranes the electron transport chain (ETC) is contained. This electron transport chain connects the shuttling of electrons across the inner membrane with the transfer of protons to create a proton gradient. This gradient allows for the synthesis of adenosine triphosphate (ATP) which is crucial for the cell to survive and is a source of energy.

Miochondria have their own set of DNA called mtDNA. This form of DNA is different then the DNA in the cell's nucleus because it is only inherited from the mother. Mutations in the DNA can cause dysfunction in proteins that help in the electron transport chain. ROS can be another source of dysfunction when they are at high levels. However, newer research has seen a correlation between more ROS and less aging and dysfunction which might be beneficial to the organism.

Although it was previously thought that outside treatments that were mildy toxic had a harmful effect on organelles, it might actually be beneficial to them. This is called mitohormesis and may actually cause an increase in cellular functioning. Therefore treatments that would originally damage the cell and the mitochondria and cause a small amount of dysfunction in oxidative phosphorylation can actually promote lifespan.

Biogenesis is the creation of organelles. Increased biogenesis has been found to reduce aging by promoting healthy aerobic respiration. Mitochondria are always undergoing biogenesis. One gene that primarily controls this process is the peroxisome proliferator-activated receptor γ co-acticator 1α (PGC-1α). The expression and post-translational modification of this gene induces nuclear respiratory factors which are partially responsible for nuclear-encoding mitochondrial proteins. Biogenesis is especially important in skeletal muscle cells in which great amounts of energy are used in a single period.

Progress Since 2013

Since the Hallmarks of Aging paper created in 2013, there have been multiple scientific research studies that further contribute to the understanding of this hallmark. Research done by Scialò et. al (2016) has found that ROS, originally thought to increase aging, actually has health benefits. The intentional increase of ROS can promote the extension of life through the reverse electron transport in the respiratory complex 1 of the ETC. This result is found in the model organism Drosophila melanogaster. This effect is seen only when there is an increase in this specific type of ROS. They can activate ROS-dependent pathways that help protect against damage and contain repair mechanisms. These pathways are thought to be how ROS contributes to longevity.

An additional study performed on Drosophila melanogaster studied the knockdown of mitochondrial ATP synthase subunit d (ATPsyn-d). This knockdown has demonstrated the ability to promote longevity. It is also shown that it is also associated with improved protein homeostasis and increased resistance to oxidative stress. It is suggested that it selectively alleviates oxidative damage from the mitochondria to maintain homeostasis in the cell and can vary in response based on acute or chronic stress and diet. The knockdown longevity is highly influenced by a high protein low carbohydrate diet. These effects were not seen in male Drosophila, which could be due to gender differences in physiology and nutrient uptake.

Another study done by Fleenor et. al (2013) showed that the spice, curcumin, has been found to reduce oxidative stress, improve vascular function, and increase lifespan. Curcumin comes from the plant Curcuma longa. This plant works by creating levels of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) which reduces oxidative stress. Cucumin was also found to scavenge for free radials, another potential cause of aging.

The lifespan of Caenorhabditis elegans has been shown to increase when parts of the ETC have been diminished in activity. Mishur et. al (2016) created a specific mitochondrial mutant (Mit) that demonstrates these effects. It is seen that the effects of longevity on Mit mutants requires hypoxia-inducible factor-1 (HIF-1). HIF-1 is a protein with α and β subunits that helps with transcription in hypoxic conditions. Without this protein all effects are abolished even under normal respiration conditions. α-ketoglutarates are found to regulate HIF-1 and can accumulate in Mit mutants. These metabolites that accumulate after mitochondrial dysfunction directly affect the lifespan of the cell by increasing HIF-1.

More research has also been done on the effects of mitohormesis and ROS in the mitochondria using the drug, Metformin. Through the process of mithormesis, metformin increases the amount of ROS. This produced a decrease in the affect of aging in Caenorhabditis elegans, Rattus norvegicus, and Mus musculus. The affect on lifespan mimics a caloric restriciton model. Metformin inhibits complex 1 of the ETC causing electron flow to slow down and breathing rate to increase. After ROS are created they can go on to form hydrogen peroxide. Peroxiredoxins help alleviate the harsh affects of hydrogen peroxide, by scavenging for these molecules.

Exercise has also been found to have a profound affect on mitochondrial health. A study conducted on rats observed immobile young and old rats as well as active rats and looked at their PGC-1α mRNA and nuclear PGC-1α protein, This mRNA and nuclear protein are used to help stimulate mitochondrial DNA replication and transcription, which helps provide the mitochondria will the tools it needs for oxidative phosphorylation. Low levels of these were cognisant of age in the old immobile rats however some of these effects were reveresed in the old active rats demonstrating the endurance exercise can reverse or slow the affects of aging in skeletal muscle.