DNM1L

Dynamin-1-like protein is a is_associated_with::GTPase that regulates is_associated_with::mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L is_associated_with::gene.

Structure
Drp1, which is a member of the is_associated_with::dynamin superfamily of proteins, consists of a GTPase and GTPase effector domain that are separated from each other by a helical segment of amino acids. There are 3 mouse and 6 human isoforms of Drp1, including a brain-specific variant.

Function
is_associated_with::Mitochondria are constantly fusing and dividing with each other, forming large, reticular networks. In humans, mitochondrial fission is regulated by Fis1 and Drp1. Fission helps facilitate is_associated_with::mitophagy, which is the breakdown and recycling of damaged mitochondria. Dysfunction in the DRP activity may result in mutated DNA or malfunctioning proteins diffusing throughout the mitochondrial system. In addition, fission results in fragmented mitochondria more capable of producing of is_associated_with::reactive oxygen species, which can disrupt normal biochemical processes inside of cells. ROS can be formed from incomplete transfer of electrons through the electron transport chain. Furthermore, fission influences calcium flux within the cell, linking Drp1 to apoptosis and cancer.

Several studies have indicated that Drp1 is essential for proper embryonic development. Drp1 knockout mice exhibit abnormal brain development and die around embryonic day 12. In neural specific Drp1 knockout mice, brain size is reduced and is_associated_with::apoptosis is increased. Synapse formation and neurite growth are also impaired. A second group of researchers generated another neural specific knockout mouse line. They found that knocking out Drp1 resulted in the appearance of large mitochondria in is_associated_with::Purkinje cells and prevented neural tube formation.

In humans, loss of Drp1 function affects brain development and is also associated with early mortality.

Interactions
The majority of knowledge about is_associated_with::mitochondrial fission comes from studies with yeast. The yeast homolog of Drp1 is dynamin-1 (Dnm1), which interacts with Fis1 through Mdv1. This interaction causes Dnm1 to oligomerize and form rings around dividing mitochondria at the so-called "constriction point". Drp1 has also been shown to interact with is_associated_with::GSK3B.

is_associated_with::Post-translational modifications to Drp1 (e.g. is_associated_with::phosphorylation) can alter its activity and affect the rate of fission.

Drp1 protein has two sites that can become phosphorylated. Depending which site is_associated_with::phosphorylation occurs, Drp1 activity changes. When Drp1 is phosphorylated at the serine-616 position, it is targeted to the mitochondrial membrane. When actively targeted to the mitochondrial membrane, it is passed along through a series of helper proteins until Drp1 ultimately binds to Fis1. In contrast, phosphorylation of serine-637 results in inactive Drp1 in the cytosol. Many proteins are able to add or remove a phosphate group at either serine-616/637 positions, linking Drp1 activity to many cellular pathways. In addition to phosphorylation Drp1 can be chemically modified and altered its function through is_associated_with::S-nitrosylation, is_associated_with::sumoylation, and is_associated_with::ubiquitination. Higher S- nitrosylation modifications of Drp1, which enhances Drp1 activity, have been observed in is_associated_with::Alzheimer’s Disease. Furthermore, Drp1 has been shown to interact with Aβ monomers, thought to play an important role in Alzheimer’s Disease, exacerbating the disease and its symptoms. Drp1 has been linked to a number of pathways and processes including cell division, is_associated_with::apoptosis, and is_associated_with::necrosis. Drp1 has been shown to stabilize is_associated_with::p53 during oxidative stress, promoting its translocation to the mitochondria and encouraging mitochondrial- related necrosis. In addition, cyclin B1- CDK activates Drp1, causing fragmentation and ensuring mitochondria are distributed to each daughter cell after mitosis. Likewise, different transcriptional controllers are able to alter Drp1 activity through gene expression and regulation. For example, is_associated_with::PPARGC1A and [HIF1A]  regulated Drp1 activity through gene expression.

Therapy
Inhibition of Drp1 has been considered for possible therapeutics for a variety of diseases. The most studied inhibitor is a small molecule named mitochondrial division inhibitor 1 (mdivi¬1). The inhibitor functions to prevent the GTPase activity of Drp1. Preventing the activation and localization to the mitochondria. Midiv-1 has been demonstrated to attenuate the effects of ischemia reperfusion injury after cardiac arrest. The treatment prevented both mitochondria fragmentation and increased cell viability. Similarly, midiv-1 has demonstrated neuroprotective effects by greatly reducing neuron death due to seizure. Furthermore, the study showed midiv-1 was capable to preventing the activation of caspase 3 by reversing the release of cytochrome c in intrinsic apoptosis. Other than directly inhibiting Drp1, certain inhibitors of proteins involved in the posttranslational modifications of Drp1 have been studied. FK506 is a calcineurin inhibitor, which functions to dephosphorylate the serine 637 position of Drp1, encouraging translocation to the mitochondria and fragmentation. FK506 was shown to also preserve mitochondrial morphology after reperfusion injury.