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Joseph P.How Mitochondrial Dynamism Orchestrates MitophagyAuthors Orian S. Shirihai, Moshi Song, Gerald W. Dorn II<a href="https://qoto.org/tags/explainpaper" class="mention hashtag" rel="nofollow noopener" target="_blank">#explainpaper</a> <a href="https://a.gup.pe/u/explainpaper" class="u-url mention" rel="nofollow noopener" target="_blank">@explainpaper</a> Understanding the Significance of Mitochondrial Fission and FusionMitochondrial dynamics refers to the movement of <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> within a cell. This includes <a href="https://qoto.org/tags/fission" class="mention hashtag" rel="nofollow noopener" target="_blank">#fission</a>, which is when mitochondria divide into two parts, <a href="https://qoto.org/tags/fusion" class="mention hashtag" rel="nofollow noopener" target="_blank">#fusion</a>, which is when two mitochondria join together, and <a href="https://qoto.org/tags/translocation" class="mention hashtag" rel="nofollow noopener" target="_blank">#translocation</a>, which is when mitochondria move from one part of the <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a> to another. This movement is important for maintaining the stability of the mitochondrial <a href="https://qoto.org/tags/DNA" class="mention hashtag" rel="nofollow noopener" target="_blank">#DNA</a>, which is the genetic material found in mitochondria, and for controlling the cell's <a href="https://qoto.org/tags/respiration" class="mention hashtag" rel="nofollow noopener" target="_blank">#respiration</a>. It can also be involved in programmed <a href="https://qoto.org/tags/CellDeath" class="mention hashtag" rel="nofollow noopener" target="_blank">#CellDeath</a>. In the <a href="https://qoto.org/tags/heart" class="mention hashtag" rel="nofollow noopener" target="_blank">#heart</a>, mitochondrial dynamics <a href="https://qoto.org/tags/protein" class="mention hashtag" rel="nofollow noopener" target="_blank">#protein</a> s, such as <a href="https://qoto.org/tags/mitofusin" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitofusin</a> s, optic <a href="https://qoto.org/tags/atrophy" class="mention hashtag" rel="nofollow noopener" target="_blank">#atrophy</a>, and dynamin-related protein, are highly expressed and play an important role in maintaining the quality of the <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>. Other roles for mitochondrial dynamics proteins in the <a href="https://qoto.org/tags/heart" class="mention hashtag" rel="nofollow noopener" target="_blank">#heart</a> include helping to move <a href="https://qoto.org/tags/calcium" class="mention hashtag" rel="nofollow noopener" target="_blank">#calcium</a> into the mitochondria and regulating the structure of the mitochondria.<a href="https://qoto.org/tags/Mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#Mitochondria</a> are organelles in cells that are responsible for producing <a href="https://qoto.org/tags/energy" class="mention hashtag" rel="nofollow noopener" target="_blank">#energy</a>. They can change their structure by breaking apart (<a href="https://qoto.org/tags/fission" class="mention hashtag" rel="nofollow noopener" target="_blank">#fission</a>) and reforming (<a href="https://qoto.org/tags/fusion" class="mention hashtag" rel="nofollow noopener" target="_blank">#fusion</a>). 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> to be broken apart and then reformed in each daughter <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>. 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>. 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 <a href="https://qoto.org/tags/protein" class="mention hashtag" rel="nofollow noopener" target="_blank">#protein</a> s.Mitochondria are <a href="https://qoto.org/tags/organelle" class="mention hashtag" rel="nofollow noopener" target="_blank">#organelle</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> in the <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>, or asymmetrical, which is when damaged components of the mitochondria are removed. The major <a href="https://qoto.org/tags/protein" class="mention hashtag" rel="nofollow noopener" target="_blank">#protein</a> that helps with mitochondrial fission is called Drp1. It is mostly found in the <a href="https://qoto.org/tags/cytosol" class="mention hashtag" rel="nofollow noopener" target="_blank">#cytosol</a>, but it needs to be recruited to the outer mitochondrial <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> 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 <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a> division, or interacting with Bcl-2–associated protein x during <a href="https://qoto.org/tags/apoptosis" class="mention hashtag" rel="nofollow noopener" target="_blank">#apoptosis</a>. 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 <a href="https://qoto.org/tags/mitosis" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitosis</a>. The most efficient way to do this is by dismantling and then reconstituting the cellular <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> network through sequential <a href="https://qoto.org/tags/organelle" class="mention hashtag" rel="nofollow noopener" target="_blank">#organelle</a> 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 <a href="https://qoto.org/tags/protein" class="mention hashtag" rel="nofollow noopener" target="_blank">#protein</a>, 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 <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a>, then incorporating additional individual <a href="https://qoto.org/tags/protein" class="mention hashtag" rel="nofollow noopener" target="_blank">#protein</a> components, and finally reconstructing the original highly organized structure, which is complicated and potentially disruptive.<a href="https://qoto.org/tags/Mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#Mitochondria</a> are small organelles in cells that can change their physical structure by undergoing fission. Fission can be symmetrical, which means the <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> 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 <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>, while asymmetrical fission is used to remove damaged mitochondria from the cell. The major <a href="https://qoto.org/tags/protein" class="mention hashtag" rel="nofollow noopener" target="_blank">#protein</a> responsible for mitochondrial fission is called Drp1. Drp1 is mostly found in the cytosol, but it needs to be recruited to the outer mitochondrial <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> to promote fission. Different factors can stimulate Drp1 to move to the outer mitochondrial <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a>, 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 <a href="https://qoto.org/tags/mitosis" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitosis</a>, 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</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 <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> /double space structure of <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>. 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 <a href="https://qoto.org/tags/GTPase" class="mention hashtag" rel="nofollow noopener" target="_blank">#GTPase</a> domain, two hydrophobic heptad repeat coiled-coil domains, and a small hydrophobic transmembrane domain. These proteins insert into the outer <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> of the <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>, and can interact with other proteins in the cytosol. The process of mitochondrial fusion is GTP-independent and reversible, but <a href="https://qoto.org/tags/GTP" class="mention hashtag" rel="nofollow noopener" target="_blank">#GTP</a> <a href="https://qoto.org/tags/hydrolysis" class="mention hashtag" rel="nofollow noopener" target="_blank">#hydrolysis</a> is essential for irreversible outer membrane fusion.<a href="https://qoto.org/tags/Mitofusins" class="mention hashtag" rel="nofollow noopener" target="_blank">#Mitofusins</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> and the <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>. 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 <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>.Membrane-by-membrane mitochondrial fusion is a process that helps to keep the structure of the inner and outer membranes of <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> 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 <a href="https://qoto.org/tags/cardiomyocyte" class="mention hashtag" rel="nofollow noopener" target="_blank">#cardiomyocyte</a> ER stress response, while interrupting Opa1-mediated IMM fusion can compromise mitochondrial function.Mitochondrial fission and fusion are important processes in <a href="https://qoto.org/tags/biology" class="mention hashtag" rel="nofollow noopener" target="_blank">#biology</a>, 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>, 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> are healthier, but this is not always the case. In some cases, mitochondrial <a href="https://qoto.org/tags/fragmentation" class="mention hashtag" rel="nofollow noopener" target="_blank">#fragmentation</a> can be beneficial, and it is important to understand the interplay between mitochondrial fragmentation and other processes, such as <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a>, in order to understand the effects of mitochondrial fission and fusion.Mitophagy is a process by which cells eat their own <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>. Mitochondria are organelles that produce energy in the form of <a href="https://qoto.org/tags/ATP" class="mention hashtag" rel="nofollow noopener" target="_blank">#ATP</a>, which is used to power most biological processes. Over time, mitochondria can become damaged and produce toxic levels of reactive oxygen species ( <a href="https://qoto.org/tags/ROS" class="mention hashtag" rel="nofollow noopener" target="_blank">#ROS</a> ). To protect the <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a> from this damage, it has developed a sophisticated system to identify and remove these dysfunctional <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>. This process is called mitophagy. <a href="https://qoto.org/tags/Mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#Mitophagy</a> is a combination of the words mitochondria and <a href="https://qoto.org/tags/autophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#autophagy</a>, 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> (the energy-producing organelles in cells) are targeted for <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a> (a process of removing damaged mitochondria from the cell), they have a relatively depolarized <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> potential before being removed. This means that the <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> have a lower electrical charge than normal, and they are less likely to be involved in <a href="https://qoto.org/tags/fusion" class="mention hashtag" rel="nofollow noopener" target="_blank">#fusion</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> (mitochondria that are about to be removed). This <a href="https://qoto.org/tags/preautophagic" class="mention hashtag" rel="nofollow noopener" target="_blank">#preautophagic</a> pool helps to explain the variation in mitochondrial <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> potential in different cell types. The process that feeds mitochondria into the preautophagic pool is important for determining how quickly <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> are removed from the <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>. Scientists have developed a technology to label individual mitochondria and track their <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> potential, which has allowed them to identify the event at which depolarized <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> are produced. This event is called asymmetrical fission, and it occurs when the daughter mitochondria produced by the fission event have different <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> 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 <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>.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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> accumulate in adult mouse hearts. This was associated with impaired <a href="https://qoto.org/tags/cardiomyocyte" class="mention hashtag" rel="nofollow noopener" target="_blank">#cardiomyocyte</a> respiration, but not with measurable alterations in <a href="https://qoto.org/tags/oxygen" class="mention hashtag" rel="nofollow noopener" target="_blank">#oxygen</a> consumption. It was later discovered that the isolation procedure used was not capturing the fragmented <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> produced by interrupting mitochondrial fusion. This led to the discovery that Mfn2 is essential to <a href="https://qoto.org/tags/Parkin" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkin</a>-mediated <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a>, which is a process that helps to maintain mitochondrial quality. Three recent papers have also implicated the mitochondrial fission protein Drp1 in cardiac <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a>, 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 <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a> depending on when it is assayed.Mfn2 and PINK1–Parkin Mitophagy Signaling is a mechanism for controlling the quality of <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> in the body. <a href="https://qoto.org/tags/PINK1" class="mention hashtag" rel="nofollow noopener" target="_blank">#PINK1</a> and <a href="https://qoto.org/tags/Parkin" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkin</a> are proteins that are linked to <a href="https://qoto.org/tags/Parkinson" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkinson</a>'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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>, which is called <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a>. <a href="https://qoto.org/tags/PINK1" class="mention hashtag" rel="nofollow noopener" target="_blank">#PINK1</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>, but when mitochondrial damage occurs, PINK1 accumulates and triggers the destruction of the damaged <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a>.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.<a href="https://qoto.org/tags/PINK1" class="mention hashtag" rel="nofollow noopener" target="_blank">#PINK1</a> is a protein that plays an important role in a process called <a href="https://qoto.org/tags/mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitophagy</a>, which is a form of quality control for mitochondria. Mutations in the <a href="https://qoto.org/tags/PINK1" class="mention hashtag" rel="nofollow noopener" target="_blank">#PINK1</a> <a href="https://qoto.org/tags/gene" class="mention hashtag" rel="nofollow noopener" target="_blank">#gene</a> have been linked to hereditary <a href="https://qoto.org/tags/Parkinson" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkinson</a>'s disease in humans, but when the PINK1 gene is deleted in mice, it does not cause the same <a href="https://qoto.org/tags/neurodegenerative" class="mention hashtag" rel="nofollow noopener" target="_blank">#neurodegenerative</a> 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 <a href="https://qoto.org/tags/neuron" class="mention hashtag" rel="nofollow noopener" target="_blank">#neuron</a> s seen in <a href="https://qoto.org/tags/Parkinson" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkinson</a>'s disease patients. This suggests that there may be other pathways that can compensate for the loss of <a href="https://qoto.org/tags/PINK1" class="mention hashtag" rel="nofollow noopener" target="_blank">#PINK1</a> and <a href="https://qoto.org/tags/Parkin" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkin</a>, such as increased transcription of other E3 <a href="https://qoto.org/tags/ubiquitin" class="mention hashtag" rel="nofollow noopener" target="_blank">#ubiquitin</a> 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, <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> 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.<a href="https://qoto.org/tags/Mitophagy" class="mention hashtag" rel="nofollow noopener" target="_blank">#Mitophagy</a> and mitochondrial dynamism are two processes that are closely connected. Mitophagy is the process of removing damaged <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> from the <a href="https://qoto.org/tags/cell" class="mention hashtag" rel="nofollow noopener" target="_blank">#cell</a>, 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 <a href="https://qoto.org/tags/Mfn2" class="mention hashtag" rel="nofollow noopener" target="_blank">#Mfn2</a> plays a role in both processes, acting as a factor for mitochondrial fusion when it is not acted on by <a href="https://qoto.org/tags/PINK1" class="mention hashtag" rel="nofollow noopener" target="_blank">#PINK1</a> and as a receptor for <a href="https://qoto.org/tags/Parkin" class="mention hashtag" rel="nofollow noopener" target="_blank">#Parkin</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> 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 <a href="https://qoto.org/tags/mitochondria" class="mention hashtag" rel="nofollow noopener" target="_blank">#mitochondria</a> healthy, which is important for preventing chronic degenerative diseases and providing opportunities for <a href="https://qoto.org/tags/therapeutic" class="mention hashtag" rel="nofollow noopener" target="_blank">#therapeutic</a> intervention.

Joseph P.<a href="https://qoto.org/tags/Articular" class="mention hashtag" rel="nofollow noopener" target="_blank">#Articular</a> <a href="https://qoto.org/tags/cartilage" class="mention hashtag" rel="nofollow noopener" target="_blank">#cartilage</a>, which is a type of <a href="https://qoto.org/tags/tissue" class="mention hashtag" rel="nofollow noopener" target="_blank">#tissue</a> found in <a href="https://qoto.org/tags/joints" class="mention hashtag" rel="nofollow noopener" target="_blank">#joints</a>, allows for nearly frictionless motion and can absorb large loads. Unfortunately, when it is damaged, it cannot repair itself. <a href="https://qoto.org/tags/Tissueengineering" class="mention hashtag" rel="nofollow noopener" target="_blank">#Tissueengineering</a> is a promising approach to repair the damage, but it falls short of creating functional tissue. This is because the tissue-engineered constructs do not have the same mechanical properties as native articular cartilage, which is due to the insufficient accumulation of <a href="https://qoto.org/tags/extracellular" class="mention hashtag" rel="nofollow noopener" target="_blank">#extracellular</a> matrix components. To address this, researchers have been exploring the use of adenosine triphosphate (<a href="https://qoto.org/tags/ATP" class="mention hashtag" rel="nofollow noopener" target="_blank">#ATP</a>) to directly harness the underlying mechanotransduction pathways responsible. ATP is a molecule that is released as a result of mechanical stimulation and acts as an autocrine/paracrine signaling <a href="https://qoto.org/tags/molecule" class="mention hashtag" rel="nofollow noopener" target="_blank">#molecule</a>. It acts on P2 receptors on the <a href="https://qoto.org/tags/plasma" class="mention hashtag" rel="nofollow noopener" target="_blank">#plasma</a> <a href="https://qoto.org/tags/membrane" class="mention hashtag" rel="nofollow noopener" target="_blank">#membrane</a> to promote extracellular matrix <a href="https://qoto.org/tags/synthesis" class="mention hashtag" rel="nofollow noopener" target="_blank">#synthesis</a>. However, high doses of ATP can lead to an increase in matrix <a href="https://qoto.org/tags/metalloproteinase" class="mention hashtag" rel="nofollow noopener" target="_blank">#metalloproteinase</a> 13 (MMP-13) activity and extracellular inorganic pyrophosphate (ePPi) accumulation, which can lead to undesirable effects such as <a href="https://qoto.org/tags/mineralization" class="mention hashtag" rel="nofollow noopener" target="_blank">#mineralization</a> of articular cartilage. Therefore, the purpose of this study is to identify the mechanism of ATP-mediated <a href="https://qoto.org/tags/catabolism" class="mention hashtag" rel="nofollow noopener" target="_blank">#catabolism</a> and to determine a therapeutic dose range to maximize the <a href="https://qoto.org/tags/anabolic" class="mention hashtag" rel="nofollow noopener" target="_blank">#anabolic</a> effect.Materials & MethodsCell Isolation: This is the process of separating cells from a tissue sample. It is usually done using <a href="https://qoto.org/tags/enzymes" class="mention hashtag" rel="nofollow noopener" target="_blank">#enzymes</a> to break down the tissue and then filtering the cells out. 3-Dimensional Culture: This is a type of <a href="https://qoto.org/tags/cellculture" class="mention hashtag" rel="nofollow noopener" target="_blank">#cellculture</a> where the cells are grown in a three-dimensional environment, rather than in a flat layer. This allows the cells to interact with each other in a more natural way.Exogenous ATP Supplementation: ATP (adenosine triphosphate) is a molecule that is important for energy production in cells. Exogenous ATP supplementation is the process of adding ATP to the cell culture from an outside source. This can help the cells to grow and function better.MMP-13 Protein Activity is a type of protein that is found inside cells. It was extracted from 3-D cultured constructs and then frozen and pulverized. It was then homogenized in a buffer solution with a protease inhibitor. After that, it was centrifuged and stored at a low temperature. To measure the amount of active MMP-13, a FRET-based assay was used. This assay uses a fluorophore and quencher to measure the amount of MMP-13 that is present. To measure the amount of ECM synthesis, a range of exogenous ATP doses were used. To measure the effect of PPi on MMP-13 activity, chondrocyte monolayer cultures were established and PPi was added to the cultures. To investigate the underlying mechanisms, inhibitors were added to the cultures. Finally, Transmission Electron <a href="https://qoto.org/tags/Microscopy" class="mention hashtag" rel="nofollow noopener" target="_blank">#Microscopy</a> (TEM) was used to determine the presence of CPPD <a href="https://qoto.org/tags/crystal" class="mention hashtag" rel="nofollow noopener" target="_blank">#crystal</a> accumulation in the engineered tissue constructs. Statistical analyses were then used to analyze the collected data.The researchers found that when they added ATP to the cultures, MMP-13 activity increased in a dose-dependent manner. This means that the more ATP they added, the more MMP-13 activity increased. They also found that the levels of PPi in the media increased significantly when they added a high dose of ATP, but the levels of PPi in the tissue did not appear to be affected. To determine the best dose of ATP to use, the researchers tested a range of doses and measured the effects on ECM synthesis (collagen and proteoglycans) and MMP-13 activity. They found that ECM synthesis and MMP-13 activity increased in response to intermediate doses of ATP, and further increased in response to higher doses of ATP.In this study, the researchers wanted to see if they could use ATP to improve tissue growth and mechanical properties without the need for mechanical loading. They found that while high doses of ATP (250 μM) had a positive effect, it also caused a catabolic response, which is when the tissue breaks down. To find the optimal dose of ATP, the researchers tested different doses (31.25, 62.5, and 125 μM) to see which one had the best effect on tissue growth and mechanical properties without causing a catabolic response.<a href="https://qoto.org/tags/Calcium" class="mention hashtag" rel="nofollow noopener" target="_blank">#Calcium</a> is an important factor in the ATP-mediated catabolism process. The researchers found that when they added 10 μM PPi to <a href="https://qoto.org/tags/chondrocyte" class="mention hashtag" rel="nofollow noopener" target="_blank">#chondrocyte</a> cultures, there was a 32% increase in MMP-13 activity compared to unstimulated controls. This effect appeared to require calcium and could be inhibited by the MEK1/2 inhibitor U0126. Additionally, TEM imaging was conducted on engineered cartilaginous tissues supplemented with 0, 62.5 and 250 μM ATP but no mineralization or CPPD crystals were observed which suggests that these doses of ATP did not cause any catabolic response due to crystal formation.The text is discussing a method of improving tissue growth and mechanical properties of engineered cartilage constructs by applying mechanical loading. However, this approach has limitations when dealing with irregular geometry and high radii of curvature. An alternative approach is to use the known mechanotransduction pathways responsible to achieve the same effect without externally applied forces. In a recent study, it was demonstrated that direct stimulation of the ATP-purinergic receptor pathway through exogenous supplementation of ATP can elicit a comparable anabolic response and be used to improve both tissue growth and mechanical properties of the developed tissue. However, high doses of ATP (250 μM) resulted in a simultaneous catabolic response characterized by an increase in MMP-13 expression, potentially due to the accumulation of ePPi. The present study determined a therapeutic dose range of exogenous ATP to maximize the anabolic response and minimize the catabolic effect of exogenous ATP. It was found that the dose range of ATP between 62.5 and 125 μM was optimal for maximizing the anabolic effect and minimizing the catabolic effect of exogenous ATP. It was also found that calcium and pyrophosphate were key factors involved in the PPi-mediated catabolic response, and that CPPD crystals could potentially be endocytosed and elicit changes through a MAPK-dependent pathway.<a href="https://qoto.org/tags/explainpaper" class="mention hashtag" rel="nofollow noopener" target="_blank">#explainpaper</a> <a href="https://qoto.org/tags/med" class="mention hashtag" rel="nofollow noopener" target="_blank">#med</a> <a href="https://qoto.org/tags/MedMastodon" class="mention hashtag" rel="nofollow noopener" target="_blank">#MedMastodon</a> The Therapeutic Potential of Exogenous Adenosine Triphosphate (ATP) for Cartilage Tissue Engineeringauthors : Jenna Usprech , Gavin Chu , Renata Giardini-Rosa , Kathleen Martin , and Stephen D. Waldman

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