Transport is mediated by two classes of molecular motor proteins, kinesin and cytoplasmic dynein. Many kinesins are expressed in neurones, corroborating their role in microtubule plus end-directed anterograde axonal transport. Of particular interest to this review are the mitochondrial binding kinesins, including the kinesin-1 family (KIF5), and KIF1Bβ, a member of the kinesin-3 family that is enriched in mouse neurones and associates with mitochondria [21,22]. Cytoplasmic dynein is the main motor protein responsible for minus end-directed (retrograde) microtubule-dependent axonal transport [23–25].

Cytoplasmic dynein is ubiquitously expressed, and is a complex molecule consisting of a dimer of two heavy chains, together with associated intermediate, light intermediate and light Panobinostat datasheet chains. Cytoplasmic dynein is not sufficient to generate retrograde movement in vivo. The adaptor protein dynactin associates with cytoplasmic dynein and is necessary for retrograde transport [26]. Mitochondria must be transported to all areas of the axon in order to generate ATP, buffer calcium and provide mitochondrial metabolites.

Mitochondria have been shown to accumulate in areas of high Kinase Inhibitor Library high throughput energy demand, such as synapses [27,28], active growth cones [29,30], nodes of Ranvier [31] and regions of protein synthesis [32]. They have also been shown to space themselves evenly along the remaining portions of axon [33]. Further, mitochondria move in a saltatory manner: starting, stopping, pausing and reversing their direction, and a large proportion of mitochondria at any time are stationary [34]. Several proteins have been implicated in the regulation of mitochondrial transport, including Milton and Miro [35–37], syntaphilin [38], and microtubule-associated proteins

[39,40]. Mitochondrial clustering in tumour necrosis factor alpha-treated cells was associated with the hyperphosphorylation of kinesin light chain, and such phosphorylation was potentially mediated by p38 kinase [41]. Other regulatory pathways of mitochondrial transport include phosphatidylinositol (4,5) biphosphate 3-oxoacyl-(acyl-carrier-protein) reductase [PtdIns(4,5)P2], which increased anterograde transport and decreased retrograde transport [19]. The PI3 kinase pathway activated by nerve growth factor has been shown to specifically regulate mitochondrial transport by causing accumulations of mitochondria in areas of nerve growth factor stimulation [42]. Furthermore, axonal transport of mitochondria correlates with membrane potential, where a depolarization of the mitochondrial membrane potential led to an increase in retrogradely transported mitochondria in dorsal root ganglia [33]. Changes to mitochondrial membrane potential could lead to the release of signalling factors that then regulate axonal transport. Additionally, increased levels of calcium lead to inhibition of mitochondrial motility, which may be a mechanism to anchor mitochondria to facilitate calcium buffering [43].