Mitochondrial fission

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Mitochondrial network (green) in two human cells (HeLa cells) HeLa mtGFP.tif
Mitochondrial network (green) in two human cells (HeLa cells)

Mitochondrial fission is the process where mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by the process of mitochondrial fusion, whereby two separate mitochondria can fuse together to form a large one. [1] Mitochondrial fusion in turn can result in elongated mitochondrial networks. Both mitochondrial fission and fusion are balanced in the cell, and mutations interfering with either processes are associated with a variety of diseases. Mitochondria can divide by prokaryotic binary fission and since they require mitochondrial DNA for their function, fission is coordinated with DNA replication. [2] Some of the proteins that are involved in mitochondrial fission have been identified and some of them are associated with mitochondrial diseases. [3] Mitochondrial fission has significant implications in stress response and apoptosis. [4]

Contents

Mechanism

FtsZ Localization

The FtsZ protein (a homologue to eukaryotic tubulin), found in many bacteria and some archaea, plays a role in mitochondrial fission. The Min system plays a role in localizing and assembling FtsZ proteins into a ring around the center of the mitochondria and some proteins tethered to the inner mitochondrial membrane also help anchor the Z ring. The Z ring is anchored at the site of constriction where division will take place. The Z ring acts as a scaffold for the deposition of septum, and it is aided in this by the proteins by FtsW, FtsI and FtsN. The translocase FtsK helps move the mtDNA away from the site of constriction.

Drp1

The Drp1 protein is a member of the dynamin family of large GTPases, transcribed from the DNM1L gene and alternative splicing leads to at least ten isoforms of Drp1 for tissue-specific fission regulation. [5] Drp1 is involved in the fission of both mitochondria and peroxisomes. The folded Drp1 monomer contains four regions: a head, neck, stalk, and tail. The head domain is a GTPase G domain. The neck is made up of three bundle signaling elements (BSEs). The trunk, which forms the stalk of the protein, involves two units which participate in three different interface interactions. One interface interaction allows for two monomers to associate into dimers whose assembly is promoted at hydrophobic patches in the stalks of each Drp1. Another interaction allows for two dimers to associate into tetramers, and the third interaction allows for tetramers to associate into higher order oligomers. [5] While Drp1 is not localized to the mitochondrial membrane, it is able to associate with the mitochondrial membrane via interactions with several adaptor proteins. In yeast cells (which are a frequent model for studying mitochondrial fission), the adaptor protein Fis1 is an outer membrane protein and associates with Mdv1 and Caf4, which in turn recruit Drp1. The mammalian FIS1 protein does not play a role in fission but instead is involved in mitophagy. [6] In human cells, there are four adaptor proteins for Drp1, these being FIS1, MiD49, MiD51, and MFF. [7] [8] In contrast, MIEF1 when bound to Drp1 might prevent mitochondrial fission and thus shift the balance towards fusion of mitochondria. [9] Regulation of Drp1 occurs through phosphorylation of its Ser616 and Ser637 residues. Phosphorylation of Ser616 promotes activity of Drp1 and therefore fission, whereas phosphorylation of Ser637 inhibits Drp1. Calcineurin is capable of dephosphorylating the Ser637 site, activated by rising levels of calcium ions. [5]

The mitochondria forms a contact site with the endoplasmic reticulum (ER), and the ER in turn associates with the mitochondria to form preconstriction sites which are necessary but insufficient for mitochondrial fission to take place. Inverted formin 2 (INF2), a protein localized on the ER, and with the help of SPIRE1C localized on the mitochondria [10] , causes actin to polymerize where bundles of actin diagonally cross each other and recruit myosin II, which assists in localizing Drp1 onto mitochondria. [11] Actin bundles are reservoirs of Drp1 proteins and their polymerization helps enable provide a pool of Drp1 proteins to assemble onto the mitochondria. Actin polymerzation also helps trigger a calcium ion influx from the ER and into the mitochondria, which results in the dephosphorylation of the Ser637 residue on Drp1 and then a scission that cleaves the inner mitochondrial membrane will. Drp1 most commonly forms rings of 16 monomers around the mitochondrial membrane, and this in turn deeply constricts the membrane. Several 16-unit Drp1 rings can assemble and form helical structures that tubulate the mitochondrial membrane. [12] Nearby rings of Drp1 will experience interactions between their G domains (or G-G interactions). G-G interactions reposition catalytic sites to cause GTP hydrolysis, and GTP hydrolysis leads to conformational changes that further assist in the final separation at the constriction site to produce two different mitochondria. The exact process by which the final separation takes place is not yet fully understood. [5]

Role of other organelles

PI(4)P needs to be delivered to the mitochondrial membrane and is necessary for fission to proceed. One mode of delivery of PI(4)P to the mitochondria-ER contact sites is from the Golgi apparatus. Golgi contain ARF1 proteins localized on their membranes, which are capable of recruiting kinases that trigger the synthesis of PI(4)P. PI(4)P is then delivered through a vesicle to mitochondria-ER contact sites. [13] Lysosomes are also often involved in but not necessary for mitochondrial fission. Contact between mitochondria and lysosomes are possible because the Rab7 protein can both form associates with lysosomes and a protein embedded on the outer mitochondrial membrane called TBC1D15. Before fission proceeds, Rab7 will dissociate from lysosomes by hydrolyzing GTP. Contact between the ER and lysosomes also takes place and these contacts also depend on Rab7. A subset of these contacts is also mediated by oxysterol binding protein related protein 1L (ORP1L). ORP1L forms associations with lysosomes via Rab7 and also forms associations with ER via VAMP-associated proteins (VAPs). Overall, this allows for three-way contact between the mitochondria, ER, and lysosomes. The ER recruits lysosomes only after Drp1 has already been recruited (whereas Drp1 itself is recruited after the preconstriction takes place). ORP1L is also required in the transfer of PI(4)P from lysosomes to the mitochondria. PI(4)P is therefore delivered to the mitochondria from both Golgi and lysosomes, and it is possible (though not currently known) that the two organelles provide PI(4)P for different purposes during fission or at different steps in the process, or whether they contribute PI(4)P for entirely distinct forms of mitochondrial fission. [14]

Peripheral and Midzone Division

Recent findings suggest that mitochondria undergo two different mechanisms of fission. In an elongated mitochondrial network, mitochondria are capable of dividing near the center (at the midzone) or towards one of the two ends (or the periphery). Midzone division and peripheral division in mitochondrial networks appears to be involved in two different cellular activities. Midzone division is promoted by biogenesis, when the cell is proliferating and more mitochondria are needed. Peripheral division results in the removal of damaged mitochondrial units from the network formed at the periphery, these mitochondria being destined for autophagy (or mitophagy), destined for destruction. Peripheral division appears to be preceded by elevated concentrations of reactive oxygen species and reduced membrane potential and pH. These two types of fission appear to be regulated by different molecular mechanisms. The adaptor protein FIS1 appears to be the involved adaptor protein recruiting Drp1 in peripheral division, whereas the adaptor MFF seems to be the involved adaptor protein recruiting Drp1 during midzone division. On the other hand, MiD49 and MiD51 appear to both be involved in both forms of division. Furthermore, the lysosomal contact sites with mitochondria only appear during peripheral division. [15]

See also

Related Research Articles

Cell biology is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and functioning of organisms. Cell biology is the study of structural and functional units of cells. Cell biology encompasses both prokaryotic and eukaryotic cells and has many subtopics which may include the study of cell metabolism, cell communication, cell cycle, biochemistry, and cell composition. The study of cells is performed using several microscopy techniques, cell culture, and cell fractionation. These have allowed for and are currently being used for discoveries and research pertaining to how cells function, ultimately giving insight into understanding larger organisms. Knowing the components of cells and how cells work is fundamental to all biological sciences while also being essential for research in biomedical fields such as cancer, and other diseases. Research in cell biology is interconnected to other fields such as genetics, molecular genetics, molecular biology, medical microbiology, immunology, and cytochemistry.

<span class="mw-page-title-main">Mitochondrion</span> Organelle in eukaryotic cells responsible for respiration

A mitochondrion is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.

<span class="mw-page-title-main">FtsZ</span> Protein encoded by the ftsZ gene

FtsZ is a protein encoded by the ftsZ gene that assembles into a ring at the future site of bacterial cell division. FtsZ is a prokaryotic homologue of the eukaryotic protein tubulin. The initials FtsZ mean "Filamenting temperature-sensitive mutant Z." The hypothesis was that cell division mutants of E. coli would grow as filaments due to the inability of the daughter cells to separate from one another. FtsZ is found in almost all bacteria, many archaea, all chloroplasts and some mitochondria, where it is essential for cell division. FtsZ assembles the cytoskeletal scaffold of the Z ring that, along with additional proteins, constricts to divide the cell in two.

<span class="mw-page-title-main">COPI</span> Protein complex

COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum (ER), where they were originally synthesized, and between Golgi compartments. This type of transport is retrograde transport, in contrast to the anterograde transport associated with the COPII protein. The name "COPI" refers to the specific coat protein complex that initiates the budding process on the cis-Golgi membrane. The coat consists of large protein subcomplexes that are made of seven different protein subunits, namely α, β, β', γ, δ, ε and ζ.

<span class="mw-page-title-main">Endosome</span> Vacuole to which materials ingested by endocytosis are delivered

Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation or can be recycled back to the cell membrane in the endocytic cycle. Molecules are also transported to endosomes from the trans Golgi network and either continue to lysosomes or recycle back to the Golgi apparatus.

The exocyst is an octameric protein complex involved in vesicle trafficking, specifically the tethering and spatial targeting of post-Golgi vesicles to the plasma membrane prior to vesicle fusion. It is implicated in a number of cell processes, including exocytosis, cell migration, and growth.

<span class="mw-page-title-main">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

The coatomer is a protein complex that coats membrane-bound transport vesicles. Two types of coatomers are known:

<span class="mw-page-title-main">MFN2</span>

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.

<span class="mw-page-title-main">PINK1</span>

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.

<span class="mw-page-title-main">DNM1L</span>

Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene and is part of the dynamin superfamily (DSP) family of proteins.

<span class="mw-page-title-main">FIS1</span> Protein-coding gene in the species Homo sapiens

Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis. By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.

<span class="mw-page-title-main">MARCH5</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5 gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.

Membrane contact sites (MCS) are close appositions between two organelles. Ultrastructural studies typically reveal an intermembrane distance in the order of the size of a single protein, as small as 10 nm or wider, with no clear upper limit. These zones of apposition are highly conserved in evolution. These sites are thought to be important to facilitate signalling, and they promote the passage of small molecules, including ions, lipids and reactive oxygen species. MCS are important in the function of the endoplasmic reticulum (ER), since this is the major site of lipid synthesis within cells. The ER makes close contact with many organelles, including mitochondria, Golgi, endosomes, lysosomes, peroxisomes, chloroplasts and the plasma membrane. Both mitochondria and sorting endosomes undergo major rearrangements leading to fission where they contact the ER. Sites of close apposition can also form between most of these organelles most pairwise combinations. First mentions of these contact sites can be found in papers published in the late 1950s mainly visualized using electron microscopy (EM) techniques. Copeland and Dalton described them as “highly specialized tubular form of endoplasmic reticulum in association with the mitochondria and apparently in turn, with the vascular border of the cell”.

<span class="mw-page-title-main">IRGs</span>

Immunity Related Guanosine Triphosphatases or IRGs are proteins activated as part of an early immune response. IRGs have been described in various mammals but are most well characterized in mice. IRG activation in most cases is induced by an immune response and leads to clearance of certain pathogens.

<span class="mw-page-title-main">Mitochondrial fission factor</span>

Mitochondrial fission factor (Mff) is a protein that in humans is encoded by the MFF gene. Its primary role is in controlling the division of mitochondria. It has also been shown to regulate peroxisome morphology.

<span class="mw-page-title-main">Mitochondrial fusion</span> Merging of two or more mitochondria within a cell to form a single compartment

Mitochondria are dynamic organelles with the ability to fuse and divide (fission), forming constantly changing tubular networks in most eukaryotic cells. These mitochondrial dynamics, first observed over a hundred years ago are important for the health of the cell, and defects in dynamics lead to genetic disorders. Through fusion, mitochondria can overcome the dangerous consequences of genetic malfunction. The process of mitochondrial fusion involves a variety of proteins that assist the cell throughout the series of events that form this process.

<span class="mw-page-title-main">Mitochondria associated membranes</span> Cellular structure

Mitochondria-associated membranes (MAM) represent a region of the endoplasmic reticulum (ER) which is reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.

<span class="mw-page-title-main">Mitochondrial dynamics protein MID49</span> Protein-coding gene in the species Homo sapiens

Mitochondrial elongation factor 2 is a protein that in humans is encoded by the MIEF2 gene.

<span class="mw-page-title-main">Divisome</span> A protein complex in bacteria responsible for cell division

The divisome is a protein complex in bacteria that is responsible for cell division, constriction of inner and outer membranes during division, and peptidoglycan (PG) synthesis at the division site. The divisome is a membrane protein complex with proteins on both sides of the cytoplasmic membrane. In gram-negative cells it is located in the inner membrane. The divisome is nearly ubiquitous in bacteria although its composition may vary between species.

References

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