How Mitochondrial Dynamism Orchestrates Mitophagy

Authors Orian S. Shirihai, Moshi Song, Gerald W. Dorn II


Understanding the Significance of Mitochondrial Fission and Fusion

Mitochondrial dynamics refers to the movement of within a cell. This includes , which is when mitochondria divide into two parts, , which is when two mitochondria join together, and , which is when mitochondria move from one part of the to another. This movement is important for maintaining the stability of the mitochondrial , which is the genetic material found in mitochondria, and for controlling the cell's . It can also be involved in programmed . In the , mitochondrial dynamics s, such as s, optic , and dynamin-related protein, are highly expressed and play an important role in maintaining the quality of the . Other roles for mitochondrial dynamics proteins in the include helping to move into the mitochondria and regulating the structure of the mitochondria.

are organelles in cells that are responsible for producing . They can change their structure by breaking apart () and reforming (). This process is complicated and energy intensive, so it is important to understand why it is necessary. One reason may be that when cells divide, the mitochondria need to be divided equally between the two daughter cells. This requires the to be broken apart and then reformed in each daughter . This process of breaking apart and reforming is more efficient than growing and budding the mitochondria. To help explain this process, the authors use the analogy of an army. Each soldier in the army is like a protein in the mitochondria, and the different units of the army are like the different parts of the . To increase the size of the army, units are added, rather than individual soldiers. This is similar to how mitochondria are modified, by adding or subtracting intact functional units, rather than individual s.

Mitochondria are s in cells that can change their physical structure by undergoing fission. Fission can be symmetrical, which is when mitochondria replicate and expand the number of in the , or asymmetrical, which is when damaged components of the mitochondria are removed. The major that helps with mitochondrial fission is called Drp1. It is mostly found in the , but it needs to be recruited to the outer mitochondrial to help with fission. Different factors can cause Drp1 to be recruited, such as phosphorylation by mitotic kinase cyclin B–cyclin-dependent-kinase (cdk) 1 complex during division, or interacting with Bcl-2–associated protein x during . Inhibiting Drp1 can protect cells from some, but not all, forms of programmed cell death.

Mitochondria, which are organelles in cells, can be partitioned in . The most efficient way to do this is by dismantling and then reconstituting the cellular network through sequential fission, distribution, and refusion. To explain this concept, the text uses an analogy of how military units are constituted and managed within an army's hierarchical organization structure. In this analogy, each soldier represents an individual respiratory complex , which are grouped together to form a squad (analogous to a respiratory complex). Squads are arranged into platoons, and approximately 6 platoons comprise a functional unit, the company (like 1 complete respiratory chain). The text suggests that it would be easier to add prefabricated supercomplexes to preexisting ones, as by fusing mitochondrial cristae, rather than trying to make a larger or different shaped mitochondrion through the wholesale incorporation of individual proteins. This is because making major structural modifications of respiratory supercomplexes on paracrystalline cristal membranes would first require destabilizing the , then incorporating additional individual components, and finally reconstructing the original highly organized structure, which is complicated and potentially disruptive.

are small organelles in cells that can change their physical structure by undergoing fission. Fission can be symmetrical, which means the are split into two equal parts, or asymmetrical, which means the mitochondria are split into two unequal parts. Symmetrical fission is used to replicate and expand the number of mitochondria in the , while asymmetrical fission is used to remove damaged mitochondria from the cell. The major responsible for mitochondrial fission is called Drp1. Drp1 is mostly found in the cytosol, but it needs to be recruited to the outer mitochondrial to promote fission. Different factors can stimulate Drp1 to move to the outer mitochondrial , such as phosphorylation by mitotic kinase cyclin B–cyclin-dependent-kinase (cdk) 1 complex. In addition, the endoplasmic reticulum (ER) is often found at the sites of mitochondrial fission. If Drp1 is not present, the mitochondria can still fragment during , suggesting that there are other mechanisms that can promote mitochondrial fission.

The text is talking about the process of mitochondrial fission, which is a process that involves connecting and separating parts of a . The author uses the metaphor of making sausage links to explain the process, but then goes on to explain that mitochondria are actually more like a turducken, which is a dish made of a chicken stuffed inside a duck stuffed inside a turkey. This creates layers of poultry, which is similar to the double /double space structure of . The author then explains that the process of mitochondrial fusion involves connecting the two mitochondria layer by layer, using proteins called mitofusins. Mitofusins have a domain, two hydrophobic heptad repeat coiled-coil domains, and a small hydrophobic transmembrane domain. These proteins insert into the outer of the , and can interact with other proteins in the cytosol. The process of mitochondrial fusion is GTP-independent and reversible, but is essential for irreversible outer membrane fusion.

are proteins that are essential for the first two stages of mitochondrial fusion, which is the process of two mitochondria joining together. This process is important for the exchange of information between the and the . If the mitofusins are deleted or suppressed, the mitochondria become abnormally small and are unable to undergo normal fusion. This can have serious implications for the health of the .

Membrane-by-membrane mitochondrial fusion is a process that helps to keep the structure of the inner and outer membranes of intact. This helps to preserve the process of oxidative phosphorylation, which is important for providing energy to cells. Without this process, molecules that can be toxic to cells can form and interrupt the electron transport chain. This process is also important for maintaining the normal shape of the crista, which is necessary for the proper assembly and functioning of electron transport chain supercomplexes. In addition, it has been shown that interrupting Mfn-mediated OMM fusion can cause a ER stress response, while interrupting Opa1-mediated IMM fusion can compromise mitochondrial function.

Mitochondrial fission and fusion are important processes in , as evidenced by the fact that mutations in genes related to these processes can cause serious diseases in humans. Altering the balance between fission and fusion can have an effect on the shape of , with more fusion leading to longer, more interconnected mitochondria, and more fission leading to shorter, less interconnected mitochondria. It is generally thought that more interconnected are healthier, but this is not always the case. In some cases, mitochondrial can be beneficial, and it is important to understand the interplay between mitochondrial fragmentation and other processes, such as , in order to understand the effects of mitochondrial fission and fusion.

Mitophagy is a process by which cells eat their own . Mitochondria are organelles that produce energy in the form of , which is used to power most biological processes. Over time, mitochondria can become damaged and produce toxic levels of reactive oxygen species ( ). To protect the from this damage, it has developed a sophisticated system to identify and remove these dysfunctional . This process is called mitophagy. is a combination of the words mitochondria and , which means "self-eating". It is a way for cells to selectively target and remove damaged mitochondria, while still keeping healthy ones. This helps to maintain the balance between having enough energy-producing and getting rid of the ones that are no longer functioning properly.

Pulse chase experiments are a type of scientific experiment used to study the behavior of molecules over time. In this particular experiment, researchers found that when (the energy-producing organelles in cells) are targeted for (a process of removing damaged mitochondria from the cell), they have a relatively depolarized potential before being removed. This means that the have a lower electrical charge than normal, and they are less likely to be involved in events (when two mitochondria join together). The time between the mitochondria becoming depolarized and being removed from the cell can range from less than an hour to about three hours, suggesting that there is a population of preautophagic (mitochondria that are about to be removed). This pool helps to explain the variation in mitochondrial potential in different cell types. The process that feeds mitochondria into the preautophagic pool is important for determining how quickly are removed from the . Scientists have developed a technology to label individual mitochondria and track their potential, which has allowed them to identify the event at which depolarized are produced. This event is called asymmetrical fission, and it occurs when the daughter mitochondria produced by the fission event have different potentials - one daughter has a higher membrane potential than the mother mitochondrion, while the other daughter has a lower membrane potential. This process of asymmetrical fission helps to separate damaged components from healthy components before they are removed from the .

The concept of mitochondrial fission and fusion and how it affects mitochondrial quality. It suggests that when the fusion factors Mfn1 and Mfn2 are both absent, unusually small and degenerated accumulate in adult mouse hearts. This was associated with impaired respiration, but not with measurable alterations in consumption. It was later discovered that the isolation procedure used was not capturing the fragmented produced by interrupting mitochondrial fusion. This led to the discovery that Mfn2 is essential to -mediated , which is a process that helps to maintain mitochondrial quality. Three recent papers have also implicated the mitochondrial fission protein Drp1 in cardiac , and it is suggested that if asymmetrical mitochondrial fission normally precedes mitophagy, then chronic suppression of fission by ablating Drp1 would have different consequences on depending on when it is assayed.

Mfn2 and PINK1–Parkin Mitophagy Signaling is a mechanism for controlling the quality of in the body. and are proteins that are linked to 's disease, and mutations in their genes were the first to be identified as causing the disease. Scientists have studied how PINK1 interacts with Parkin, and how this interaction can lead to the destruction of damaged , which is called . is like an ignition switch that senses when mitochondrial damage has occurred, and then activates Parkin-mediated mitophagy. PINK1 is normally not present in healthy , but when mitochondrial damage occurs, PINK1 accumulates and triggers the destruction of the damaged .

PINK1 is a protein that accumulates on damaged mitochondria and helps to promote mitophagy, which is the process of getting rid of damaged mitochondria. PINK1 does this by inducing the cytosolic protein Parkin to move to the mitochondria and ubiquitinate proteins on the outer membrane of the mitochondria. This helps to prevent the spread of damage from the damaged mitochondria to the healthy ones. PINK1 also inhibits the fusion of the damaged mitochondria. There are different theories about the biochemical events that cause Parkin to move to the mitochondria and stop the fusion. It is thought that PINK1 phosphorylates Parkin on certain sites, which helps Parkin bind to the mitochondria. It is also thought that PINK1 phosphorylates ubiquitin, which helps Parkin bind to the mitochondria and ubiquitinate proteins on the outer membrane. Finally, it is thought that PINK1 phosphorylates Mfn2, which helps Parkin bind to the mitochondria and ubiquitinate proteins on the outer membrane. All of these processes help to promote mitophagy and prevent the spread of damage from the damaged mitochondria to the healthy ones.

is a protein that plays an important role in a process called , which is a form of quality control for mitochondria. Mutations in the have been linked to hereditary 's disease in humans, but when the PINK1 gene is deleted in mice, it does not cause the same pattern seen in humans. Even when the genes for PINK1, Parkin, and DJ-1 are all deleted in mice, it still does not cause the same loss of dopaminergic s seen in 's disease patients. This suggests that there may be other pathways that can compensate for the loss of and , such as increased transcription of other E3 ligases in the hearts of Parkin-knockout mice.

The text is discussing the idea of mitochondrial quality control pathways, which are processes that help keep mitochondria healthy. The text is suggesting that there may be alternate pathways that can be used to maintain mitochondrial health, rather than waiting until the mitochondria are completely depolarized before triggering their removal. It is comparing this idea to the idea of maintaining a car, where it is better to perform regular maintenance and repairs rather than waiting until the car is completely broken down before replacing it.

Like a car, mitochondria can be maintained through preventative maintenance, such as replacing worn parts, and that more serious damage can be repaired by removing and replacing individual components. It also suggests that, like a car, can be repaired by removing and replacing damaged parts, but on a smaller scale. The different types of maintenance and repair may be part of a continuum, rather than distinct categories.

and mitochondrial dynamism are two processes that are closely connected. Mitophagy is the process of removing damaged from the , while mitochondrial dynamism is the process of mitochondria fusing together and separating. The two processes work together to keep the cell healthy by eliminating damaged mitochondria and preventing healthy mitochondria from being contaminated by the damaged ones. The protein plays a role in both processes, acting as a factor for mitochondrial fusion when it is not acted on by and as a receptor for when it is. This suggests that the two processes are mutually exclusive, meaning that they cannot happen at the same time. This helps to protect healthy from being contaminated by the damaged ones. Finally, the involvement of PINK1 and Parkin in multiple mitochondrial quality control mechanisms shows that there are multiple ways to keep the healthy, which is important for preventing chronic degenerative diseases and providing opportunities for intervention.

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