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. 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. Some of the proteins that are involved in mitochondrial fission have been identified and some of them are associated with mitochondrial diseases. Mitochondrial fission has significant implications in stress response and apoptosis.
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. 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. 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. In human cells, there are four adaptor proteins for Drp1, these being FIS1, MiD49, MiD51, and MFF. In contrast, MIEF1 when bound to Drp1 might prevent mitochondrial fission and thus shift the balance towards fusion of mitochondria. 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.