y between cells and even within a cell, depending on the metabolic states. Cardiomyocytes and neurons, due to their high energy demands, have greater amounts. Mitochondria are dynamic and form reticular networks to assure efficient distribution of mitochondrial DNA (mtDNA) and proteins. The fission and fusion of mitochondria are features of mitochondria dynamics along with their trafficking along microtubule routes in higher organisms (actin in yeast). Mitochondria dynamics and the mitochondrial autophagy (mitophagy) pathways are intimately connected. Fission is believed to be a pre-requisite for mitophagy, allowing for the delineation of individual, damaged mitochondria while mitophagy targets components of the fusion apparatus and of transport for degradation. Of the ~1,500 mitochondrial proteins, only 13 are encoded in the mtDNA, the rest (~99%), have to be imported. As such, the mitochondrial protein import pathway impacts on every aspect of mitochondrial function, including mitochondria dynamics and autophagy. The pathways of mitochondria dynamics are presented here.

The fission and fusion of mitochondria are ordered, energy-intensive events. Fission is thought to occur both in a symmetric fashion that allows mitochondria to divide and grow/expand or asymmetrically, promoting isolation of defective mitochondria. Fission may occur shortly after a fusion event (in transient fusion) to allow segregation of mitochondria with healthy membrane potential from those with less than optimal membranes. The mitochondria with the healthy membrane could then undergo fusion. The main players in both the fission and the fusion pathways are dynamin-related GTPases, aided by a selected assortment other proteins that could act as receptors/scaffolds, or adaptors/effectors. Distribution of mitochondria, the transport of organelles to sites of energy demand occurs along the cytoskeleton, via microtubules. The neuronal synapses have some of the highest energy demands; the unique structure of neurons poses unique challenges for molecular transport and the balance between mobile and stationary mitochondria

Mitochondria fission pathway
In mammals, the main effector of fission is the Dnm1l (known as Drp1) GTPase. The cytosolic protein needs to be recruited to the outer mitochondrial membrane (OMM); the factor leading to Dnm1l translocation may differ depending on the events dictating fission. The protein contains an N-terminal GTPase domain, middle and variable domains, followed by the C-terminal GTP effector domain (GED). The GED interacts with the middle of adjacent molecules assembling into ring-like, spiral complexes that constrict in a GTP-dependent manner and promote scission and separation (click to link to a structural page). Several OMM proteins, such as Fis1, Mtfp1 (Mtp18), Gdap1 or Sh3glb1 (endophilin B1), are known to play a role in Dnm1l mediated fission, although the mechanisms are not well understood. Others, like Mff, Mief2 (MiD49) and Mief1 (MiD51) have been proposed to play a role in recruitment and activation. They interact with Dnml1 but the exact role of the interaction needs to be determined. Post-translational modifications of Dnml1 like phosphorylation, sumoylation and ubiquitination can affect its function, translocation and/or fate; their precise role is being investigated. Constriction/fission sites are often marked by mitochondria-Endoplasmic Reticulum (ER) contacts. Mutations in several components of the fission pathway have been associated with human diseases.

Mitochondria fusion pathway
Fusion is dependent upon the mitofusin GTPases Mfn1 and 2 at the outer mitochondrial membrane (OMM) and Opa1 at the inner mitochondrial membrane (IMM). Mfn1/2 span twice the OMM thus having the C-terminal coiled-coil domain and the N-terminal GTPase domain exposed to the cytosol. Mitofusins form homo- and hetero-oligomers via their coiled coil domain; trans-association on adjacent mitochondria mediates fusion ( click to link to a structural page). The two proteins are not equivalent: Mfn1 has a higher GTP-dependent tethering activity than Mfn2, Mfn2 is enriched at ER-mitochondria interface. Mitchondrial phospholipase D hydrolyzes cardiolipin (CL)on OMM; the resulting phosphatidic acid can induce membrane curvature and is known to promote fusion, although the mechanisms are not well understood. There are several isoforms of Opa1 and both the long and short isoforms play a role in fusion. CL, the signature lipid of IMM, increases the GTPase activity of IMM resident Opa1. In addition to fusion, Opa1 is involved in the maintenance of mitochondria cristae. Prohibitin2 and Stoml2 (known as Slp-2_ are thought to act as scaffolds. Parkin, in the mitochondrial autophagy pathway (mitophagy), targets Mfn1/2 to proteosomal degradation, thus removing the inhibitory effect fusion would have on mitophagy. Fusion can be complete or transient; a fission event will follow fusion termed 'kiss-and-run'. Mutations in several components of the fusion pathway have been associated with human diseases.

Mitochondria transport pathway
Transport and distribution of mitochondria assure that the metabolic needs of the cells are properly met. Mitochondria delivery to neuronal synapses - sites of the highest energy demand, provides a paradigm. The provision or replenishment of functional mitochondria, removal of the dysfunctional, damaged mitochondria and immobilization of motile mitochondria, as necessary are important aspects of mitochondria transport. Movement along the microtubules (MT) is mediated by motor proteins that use the power derived from ATP hydrolysis to move their cargo; kinesins drive anterograde movement, cytoplasmic dyneins drive the retrograde one. The polarity of MT provides directional cues; in neuronal axons, MT have their plus ends oriented distally and the minus ends oriented towards the soma. Motor proteins rely on adaptor proteins to link to mitochondria. A major adaptor is Trak/Milton (Trak1 and 2) with binding sites for kinesin and dynein, thus being able to promote bi-directional movement. Several other adaptors have been suggested. Miro (Rhot1 and 2) is an OMM resident that anchors the transport system(s) to mitochondria. The two are members of the Rho family of GTPases and bind Trak/Milton. Immobilization of motile mitochondria at firing synapses is achieved via anchoring by syntaphilin and by Miro calcium-sensing that inactivates or disassemble the transport complex (Miro proteins also have EF-hands, Ca-binding motifs). In addition to providing the necessary ATP, the stationary mitochondria also acts as a calcium buffering system. Miro is a target of Pink1-Parkin, the main quality control system of mitochondrial autophagy. Depolarized mitochondria are not delivered to the terminals and studies suggest that turnover of Miro promotes retrograde movement to the soma , the site of mature acidic lysosome. Fusion of the autophagosome with the lysosome is the final stage of autophagy followed by cargo degradation. The retrograde transport is mediated by the dynein complex and Trak/Milton may be the adaptor. Dynein is a multisubunit complex consisting of the heavy chain containing the motor domain and several intermediate and light chain subunits. Dynactin, a multisubunit complex, binds dynein and MT via its large subunit, Dctn1, known as p150; dynein and dynactin are necessary for retrograde transport. Defective mitochondria transport has been associated with neurodegenerative diseases. To see the ontology report for annotations, GViewer and download, click here...(less)