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 by which mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by mitochondrial fusion, where two mitochondria fuse together to form a larger one. [1] Fusion can result in elongated mitochondrial networks. In healthy cells, mitochondrial fission and fusion are balanced, and disruptions to these processes are linked to various diseases. Mitochondrial fission is coordinated with the mitochondrial DNA replication process. [2] Some of the proteins involved in mitochondrial fission have been identified, and mutations in some of these proteins are associated with mitochondrial diseases. [3] Mitochondrial fission plays a role in the cellular stress response and in apoptosis (programmed cell death). [4]

Contents

Mechanism

Drp1

The Drp1 protein, a member of the dynamin family of large GTPases, is transcribed from the DNM1L gene. Alternative splicing produces at least ten isoforms of Drp1, which regulate tissue-specific mitochondrial fission. [5] Drp1 is involved in the fission of both mitochondria and peroxisomes. The folded Drp1 monomer consists of four regions: a head, neck, stalk, and tail. The head region is the GTPase (G) domain, while the neck is composed of three bundle signaling elements (BSEs). The stalk consists of two units that participate in three interface interactions. These interactions allow the assembly of Drp1 into higher-order oligomers: first, two monomers associate into dimers through hydrophobic patches on the stalk, then two dimers associate into tetramers, and finally, tetramers can assemble into larger oligomeric structures. [5]

Although Drp1 is not localized to the mitochondrial membrane, it can associate with the mitochondrial membrane via interactions with several adaptor proteins. In yeast cells (a common model for studying mitochondrial fission), the outer membrane protein Fis1 associates with Mdv1 and Caf4, which in turn recruit Drp1. In mammals, FIS1 does not participate in fission but instead plays a role in mitophagy. [6] In human cells, four adaptor proteins can help recruit Drp1 to the mitochondria: FIS1, MiD49, MiD51, and MFF. [7] [8] MiD51, also named MIEF1, can inhibit Drp1's function, favoring mitochondrial fusion instead of fission. [9]

Regulation of Drp1 occurs by the phosphorylation of its Ser616 and Ser637 residues. Phosphorylation at Ser616 promotes Drp1 activity and thus mitochondrial fission, while phosphorylation at Ser637 inhibits Drp1. Calcineurin, activated by increased calcium ion levels, can dephosphorylate the Ser637 site, thus promoting fission. [5]

Mitochondria form contact sites with the endoplasmic reticulum (ER), where preconstriction sites are created, which are necessary but not sufficient for fission. Inverted formin 2 (INF2), an ER-localized protein, with the help of SPIRE1C on the mitochondria, [10] promotes actin polymerization. Bundles of actin cross diagonally at these sites, recruiting myosin II, which assists in localizing Drp1 to the mitochondria. [11] Actin bundles serve as reservoirs of Drp1 proteins, providing a pool for assembly onto the mitochondrial surface. Actin polymerization also triggers calcium ion influx from the ER into the mitochondria, resulting in the dephosphorylation of Ser637 on Drp1, leading to mitochondrial fission.

Drp1 typically assembles into rings composed of 16 monomers that encircle the mitochondrial membrane and constrict it. Several Drp1 rings can form helical structures that tubulate the membrane. [12] The G domains of adjacent Drp1 monomers interact (G-G interactions), repositioning catalytic sites to induce GTP hydrolysis, which drives conformational changes. These changes assist in the final membrane scission, producing two separate mitochondria. The exact mechanism of final membrane separation is still not fully understood. [5]

Role of other organelles

Phosphatidylinositol 4-phosphate (PI(4)P) must be delivered to the mitochondrial membrane for fission to proceed. One method of PI(4)P delivery to mitochondria-ER contact sites is via the Golgi apparatus. The Golgi contains ARF1 proteins localized on its membranes, which recruit kinases that promote the synthesis of PI(4)P. PI(4)P is then delivered to the mitochondria-ER contact sites via vesicles derived from the Golgi apparatus. [13]

Lysosomes are also frequently involved in mitochondrial fission, though they are not essential for the process. Contact between mitochondria and lysosomes is mediated by the Rab7 protein, which associates with lysosomes and a mitochondrial outer membrane protein called TBC1D15. Before fission proceeds, Rab7 dissociates from lysosomes by hydrolyzing GTP. Additionally, contacts between the ER and lysosomes occur, which also depend on Rab7. A subset of these contacts is mediated by oxysterol-binding protein-related protein 1L (ORP1L). ORP1L interacts with lysosomes via Rab7 and with the ER via VAMP-associated proteins (VAPs). This forms three-way contact sites between the mitochondria, ER, and lysosomes.

Lysosomes are recruited by the ER only after Drp1 has been recruited to the mitochondrial membrane (Drp1 recruitment occurs after preconstriction). ORP1L is also necessary for transferring PI(4)P from lysosomes to mitochondria. Therefore, PI(4)P is delivered to the mitochondria from both the Golgi and lysosomes. It remains unclear whether the two organelles supply PI(4)P for different purposes during mitochondrial fission, at different steps in the process, or if they contribute to distinct forms of mitochondrial fission altogether. [14]

Peripheral and Midzone Division

Recent findings suggest that mitochondria undergo two distinct mechanisms of fission. In an elongated mitochondrial network, fission can occur either near the center (at the midzone) or towards one of the two ends (the periphery). Midzone and peripheral divisions appear to be associated with different cellular processes. Midzone division is linked to mitochondrial biogenesis, which occurs when the cell is proliferating and requires an increased number of mitochondria. In contrast, peripheral division is associated with the removal of damaged mitochondrial units from the network, with these mitochondria being targeted for autophagy or mitophagy, leading to their degradation.

Peripheral division is often preceded by elevated concentrations of reactive oxygen species (ROS), as well as reduced membrane potential and pH. These two types of fission are regulated by distinct molecular mechanisms. During peripheral division, the adaptor protein FIS1 is primarily responsible for recruiting Drp1, while during midzone division, the adaptor protein MFF plays a key role in Drp1 recruitment. Interestingly, MiD49 and MiD51 are involved in both forms of division. Additionally, lysosomal contact sites with mitochondria are only observed 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 the 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">Endomembrane system</span> Membranes in the cytoplasm of a eukaryotic cell

The endomembrane system is composed of the different membranes (endomembranes) that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryotes the organelles of the endomembrane system include: the nuclear membrane, the endoplasmic reticulum, the Golgi apparatus, lysosomes, vesicles, endosomes, and plasma (cell) membrane among others. The system is defined more accurately as the set of membranes that forms a single functional and developmental unit, either being connected directly, or exchanging material through vesicle transport. Importantly, the endomembrane system does not include the membranes of plastids or mitochondria, but might have evolved partially from the actions of the latter.

<span class="mw-page-title-main">Cytokinesis</span> Part of the cell division process

Cytokinesis is the part of the cell division process and part of mitosis during which the cytoplasm of a single eukaryotic cell divides into two daughter cells. Cytoplasmic division begins during or after the late stages of nuclear division in mitosis and meiosis. During cytokinesis the spindle apparatus partitions and transports duplicated chromatids into the cytoplasm of the separating daughter cells. It thereby ensures that chromosome number and complement are maintained from one generation to the next and that, except in special cases, the daughter cells will be functional copies of the parent cell. After the completion of the telophase and cytokinesis, each daughter cell enters the interphase of the cell cycle.

<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 the 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.

In cell biology, a granule is a small particle barely visible by light microscopy. The term is most often used to describe a secretory vesicle containing important components of cell phyisology. Examples of granules include granulocytes, platelet granules, insulin granules, germane granules, starch granules, and stress granules.

<span class="mw-page-title-main">Phagosome</span> Vesicle formed around a particle engulfed by a phagocyte via phagocytosis

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> Protein-coding gene in the species Homo sapiens

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">DNM1L</span> Protein-coding gene in humans

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.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

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”.

Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles. Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise.

<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> Protein-coding gene in the species Homo sapiens

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. Mitochondrial morphology changes by continuous fission in order to create interconnected network of mitochondria. This activity is crucial for normal function of mitochondria. Mff is anchored to the mitochondrial outer membrane through the C-terminal transmembrane domain, extruding the bulk of the N-terminal portion containing two short amino acid repeats in the N-terminal half and a coiled-coil domain just upstream of the transmembrane domain into the cytosol. 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">Phomoxanthone A</span> Chemical compound

The mycotoxin phomoxanthone A, or PXA for short, is a toxic natural product that affects the mitochondria. It is the most toxic and the best studied of the naturally occurring phomoxanthones. PXA has recently been shown to induce rapid, non-canonical mitochondrial fission by causing the mitochondrial matrix to fragment while the outer mitochondrial membrane can remain intact. This process was shown to be independent from the mitochondrial fission and fusion regulators DRP1 and OPA1.

<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">Gia Voeltz</span> American cell biologist

Gia Voeltz is an American cell biologist. She is a professor of Molecular, Cellular and Developmental Biology at the University of Colorado Boulder and a Howard Hughes Medical Institute Investigator. She is known for her research identifying the factors and unraveling the mechanisms that determine the structure and dynamics of the largest organelle in the cell: the endoplasmic reticulum. Her lab has produced paradigm shifting studies on organelle membrane contact sites that have revealed that most cytoplasmic organelles are not isolated entities but are instead physically tethered to an interconnected ER membrane network.

References

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