Mitochondria continually change shape through the combined actions of fission, fusion, and movement along cytoskeletal tracks. The lengths of mitochondria and the degree to which they form closed networks are determined by the balance between fission and fusion rates. These rates are influenced by metabolic and pathogenic conditions inside mitochondria and by their cellular environment. Fission and fusion are important for growth, for mitochondrial redistribution, and for maintenance of a healthy mitochondrial network. In addition, mitochondrial fission and fusion play prominent roles in disease-related processes such as apoptosis and mitophagy. Three members of the Dynamin family are key components of the fission and fusion machineries. Their functions are controlled by different sets of adaptor proteins on the surface of mitochondria and by a range of regulatory processes.
Members of the kinetic family of median mitochondrial division and fusion
The main mitochondrial fission and fusion proteins are members of the Dynamin family (Figure. 1). The first mitochondrial Dynamin was named Mgm1, because mutations in the yeast gene cause a mitochondrial genome maintenance defect. This mitochondrial DNA (mtDNA) distribution defect was later shown to be a secondary consequence of defects in mitochondrial inner membrane fusion. Localization studies also showed that Mgm1 is anchored in the mitochondrial inner membrane with the bulk of the protein facing the mitochondrial inner membrane space. A human homolog of Mgm1 was discovered through sequence homologies and through genetic mapping of a late onset neurodegenerative eye disease, named Dominant Optic Atrophy (DOA). The human homolog was named Opa1 for the optic atrophy defects.
Figure 1. Functions of the mitochondrial Dynamin family members.
The Drp1 homologs have a domain structure that is characteristic of the Dynamin family (Figure. 2). Each one has a GTPase domain followed by a middle domain, a variable domain, and a GTPase effector domain (GED). The variable domain, also referred to as insert B, is generally required for binding to the target membrane. In the fission Dynamins, this domain binds to adaptor proteins on the mitochondrial surface. The lipid-binding domain in the fusion proteins, Mgm1 and Opa1, is specific for cardiolipin, whereas the outer membrane fusion proteins, Fzo1 and Mitofusins, each have two trans-membrane segments that serve as membrane anchors.
Figure 2. Schematic diagrams of fission and fusion proteins.
Regulation of mitochondrial fission through phosphorylation and ubiquitination
Mitochondrial fission proteins are regulated by a range of protein modifications, including phosphorylation, ubiquitination, sumoylation, and nitrosylation. Different kinases control the activities of Drp1 by phosphorylating this protein at three different sites. These sites include Ser616, which is phosphorylated by protein kinase C (PKC) δ, Rock kinase, CDK1/Cyclin B or CAMK-Ia and Ser637, which is phosphorylated by protein kinase A (PKA). Phosphorylation of Ser616 is likely to activate fission, because it promotes binding to other fission proteins, whereas phosphorylation of Ser637 could be an inactivating step. The third site in Drp1 is Ser693, which is phosphorylated by GSK3β to inhibit mitochondrial fission during apoptosis. This residue is in the GED, where it most likely affects Drp1 oligomerization or GTP hydrolysis.
Other effects of fusion Mitophagy proteins
The phenotypic effects of mutations in the mitochondrial inner and outer membrane fusion proteins are significantly different. Yeasts Fzo1 and Mgm1 noticed this, with Mgm1 appearing to have other functions in helping to preserve mtDNA and ista morphology. Mutations in similar C. elegans and Drosophila proteins have also noted differences in viability and tissue-specific effects. Although homozygous mutations in mice are fatal, there are differences in the most affected stages and in heterozygous animals. Humans with pathogenic mutations in mitochondrial fusion proteins or Opa1 are usually heterozygous, but the diseases caused by these mutations are different: Opa1 mutations cause optic nerve atrophy through the gradual loss of retinal ganglion cells, while Mfn2 mutations cause Forms of peripheral neuropathy.
1. Van d B A M.; et al. Mechanisms of Mitochondrial Fission and Fusion. Cold Spring Harbor Perspectives in Biology, 2013, 5(6): a011072-a011072.