For the various cellular motors to transport mitochondria, they need to consume ATP, and the motors need to be attached to

the mitochondria Lenvatinib datasheet via adaptor molecules (Milton/TRAK, Miro, and Syntabulin). Regulation of mitochondrial movement occurs both at the level of motor function, through local alterations of ADP/ATP ratio, and at the level of the attachment of mitochondria to the motors and the tracks they move along, through local changes in [Ca2+]i (Brough et al., 2005; Mironov, 2006). Postsynaptically, increased energy expenditure on glutamate-induced ion fluxes leads to a local rise in [ADP] and a fall of [ATP]. This decreases the energy available to the motor molecules transporting mitochondria, and rebinding of ADP to the motors in particular slows their movement (Mironov, 2007). A similar phenomenon Protease Inhibitor Library solubility dmso occurs in axons

in response to ATP use on pumping out of Na+ at the Ranvier node (Zhang et al., 2010) and so is also expected during energy use on Ca2+ pumping and vesicle trafficking in presynaptic terminals (Figure 5). In addition to this energetic limitation of mitochondrial movement, the rise in [Ca2+]i that occurs presynaptically via voltage-gated Ca2+ channels, and postsynaptically via Ca2+ influx through NMDA receptors (and possibly Ca2+-permeable AMPA/kainate receptors), leads to a parking of mitochondria at the active synapse. Wang and Schwarz (2009) found that a rise in axonal [Ca2+]i in hippocampal neurons leads to mitochondrial stopping, following Ca2+ binding to the adaptor protein Miro, which resulted in kinesin motors detaching from their microtubule tracks (Figure 5, presynaptic side; Ca2+ entry into the mitochondria may be needed for this to occur: Chang Sitaxentan et al., 2011). A similar arrest of mitochondrial movement in dendrites is triggered by Ca2+ entering through postsynaptic

NMDA receptors (Rintoul et al., 2003; MacAskill et al., 2009). In this case the proposed mechanism differed: Ca2+ binding to Miro was suggested to detach Miro from the kinesin motor (Figure 5, postsynaptic side). Calcium may also regulate mitochondrial transport by myosin, since Ca2+ stimulates myosin-actin ATPase activity but also (presumably at higher [Ca2+]i) decreases transport by dissociating calmodulin from myosin (Lu et al., 2006; Taylor, 2007). Speculatively, therefore, a small [Ca2+]i rise may stop microtubule-based transport (MacAskill et al., 2009; Wang and Schwarz, 2009) and promote local actin-based transport, until the mitochondrion encounters a higher [Ca2+]i, which will stop actin-based transport.