User:KantasisG/Mitochondrial dynamics

Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. In a wild-type cell, high rates of fusion and fission are independent events, which constantly change the identity of individual mitochondria. Therefore fusion and fission seems to be required to maintain mitochondrial function, as independent and different mechanisms. A further two important aspects of mitochondrial dynamics beyond fusion and fission is the motility of mitochondria and mitophagy. It has been proved that perturbations in mitochondrial dynamics can lead to distinctive defects in neurons. These dynamic processes regulate mitochondrial function by enabling mitochondrial recruitment to critical subcellular compartments, content exchange between mitochondria, mitochondrial shape control, mitochondrial communication with the cytosol and mitochondrial quality control. Even though, these four processes are independent, it is clear that any interactions will be critically important in neurons. For example defects in both fusion and fission have been shown to decrease mitochondrial movement. The large tangle of highly interconnected mitochondria in fission-deficient cells prevents efficient movement, especially into small pathways such as neuronal processes.

Considering the latest researches, disruptions in the regulation of mitochondrial dynamics, low energy production, increased reactive oxygen species and mtDNA damage are relevant to human diseases, mainly in neurogenerative diseases and cancer. Since many neurodegenerative diseases cause mitochondria to malfunction, it may be important to focus on developing methods to repair and restore mitochondria. Already a few strategies are being developed that open up ways for manipulating mitochondrial functions and may allow for the selective protection or eradication of neurons in the treatment of neurodegenerative diseases.

Fusion
Fusion is likely to protect function by providing a chance for mitochondria to mix their contents, thus enabling protein complementation, mtDNA repair and equal distribution of metabolites, helping the isolation of damaged mitochondrial segments and promoting their autophagy.

Fission
Fission acts in order to facilitate equal segregation of mitochondria into daughter cells during cell division and to enhance distribution of mitochondria along cytoskeletal tracks. The failure in this biological machinery may also promote apoptosis.

Mitophagy
Mitophagy denotes the degradation of mitochondria through autophagy. Although the existence of mitophagy has been known for some time, it has been unclear whether mitochondria are randomly or selectively targeted for mitophagy. Several recent findings indicate that mitophagy can selectively degrade defective mitochondria [17]. In yeast cells, mitophagy is regulated independently from bulk autophagy. Mitochondria that are damaged by a laser irradiation in hepatocytes are selectively removed by mitophagy. Studies in pancreatic b-cells and COS7 cells show that mitochondrial fission can yield uneven products, with one depolarized daughter mitochondrion and one hyperpolarized mitochondrion (27). Such depolarized mitochondria are much less likely to fuse, have reduced levels of OPA1 protein, and are eventually autophagocytosed. This mitophagy is dependent on loss of fusion and the presence of fission, because OPA1- overexpression, Fis1 RNAi, and Drp1 dominant-negative expression all reduce levels of mitophagy. When mitophagy is thus compromised, oxidized proteins accumulate, and cellular respiration and insulin secretion decrease. It is important to note that although mitochondrial fragmentation is permissive for mitophagy, it is not a sufficient signal for mitophagy (27,31).

Mitochondrial motility
Mitochondrial motility is critically important in highly polarized cells, such as neurons (32), which require mitochondria at sites distant from the cell body, but can also be crucial to cellular function in smaller cells (33). Defects in both fusion and fission have been shown to decrease mitochondrial movement. Presumably, the large tangle of highly interconnected mitochondria in fission-deficient cells prevents efficient movement, especially into small pathways such as neuronal processes (34,35). Empirically, however, fusion-deficient mitochondria display loss of directed movement, instead hovering in a manner reminiscent of Brownian motion (6). In neurons lacking mitochondrial fusion, both increased mitochondrial diameter due to swelling and aggregations of mitochondria seem to block efficient entry into neurites, resulting in a dearth of mitochondria in axons and dendrites (36). These defects result in improperly developed neurons or gradual neurodegeneration. Mitochondrial transport in mammalian cells is largely microtubule based (32). How this mitochondrial transport apparatus interacts with the fusion/fission machinery is unclear, but most likely involves indirect interactions. Deletion of Miro in yeast greatly affects mitochondrial morphology without disrupting mitochondrial fusion or fission (42).

Neurodegenereative Diseases
Aside from diseases such as DOA and CMT2A caused by perturbation of mitochondrial fusion and fission, mitochondrial dynamics seems to impact a wide variety of human diseases through interactions with other cellular processes. Many of these diseases are neurodegenerative and affect many distinct regions of the brain as well as the peripheral nervous system, again emphasizing the importance of mitochondrial function in maintaining healthy neurons. The main problems associated with mitochondrial disease, such as low energy, free radical production and lactic acidosis, can result in a variety of symptoms in many different parts of the body, including the nervous system, digestive tract, eyes, skeletal muscle, heart, liver, kidneys, and pancreas. After years of intense studies, a considerable number of scientific researches demonstrated the important role of mitochondrial dysfunction and oxidative stress to development of the more common neurogenerative diseases, like Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Recent studies have already proved the significant connection between mitochondrial dysfunction and human diseases and the disruptions of energy production due to inappropriate topological structure. It is proved that the creation of electric complexes into the inner mitochondrial membrane due to the unusual concentration of protons disrupts the normal flow of electrons and the production of ATP [alexiou]. This phenomenon can be characterized as an ‘electric thromboses’ and the superconductivity in the flow of electrons will be cancelled. Based on these phenomenon, a new model have been proposed for the mitochondrial dysfunction in neurogenerative diseases due to the high energy concentration in mitochondrial inner membrane. This model represents the internal mitochondrial membrane as a natural superconductor, where electrical resistance of exactly zero occurs in certain temperature [alexiou]. The electric potential across the inner membrane in terms of radioactive 42K+ ions, can be expreesed using the Nernst equation:

$$E = -59\log{[K_{in}] \over [K_{out}]}$$

where $$ [K_{in}] $$ is the concentration of radioactive K+ icons in the matrix and $$ [K_{out}] $$ is the concentration of radioactive K+ icons in the surrounding medium. Also we can calculate the proton motive force (pmf) in millivolts:

$$pmf= \Psi-({{RT}\over{F}}* \Delta pH)= \Psi - 59 \Delta pH$$

where Ψ is the electric potential across the inner membrane,R is the gas constant, T is the temperature, F is the Faraday constant and ΔpH is the pH gradient. Based on this model, a first solving approach should be the use of large electrical load or a larger potential difference to impel electrons into the transmembrane space.