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Correspondence to Zu-Hang Sheng: [email protected] Abbreviations used in this paper: KIF5, kinesin-1 family; MT, microtubule. Introduction Mitochondria are cellular power plants that convert chemicals into ATP through coupled electron transport chain and oxidative phosphorylation. A cortical neuron in human brain utilizes up to 4.7 billion ATP molecules per second to power various biological functions (Zhu et al., 2012). Constant ATP supply is essential for nerve cell survival and function (Nicholls and Budd, 2000). Mitochondrial ATP production supports synapse assembly (Lee and Peng, 2008), generation of action potentials (Attwell and Laughlin, 2001), and synaptic transmission (Verstreken et al., 2005). Synaptic mitochondria maintain and regulate neurotransmission by buffering Ca (Medler and Gleason, 2002; David and Barrett, 2003). In addition, mitochondria sequester presynaptic Ca transients elicited by trains of action potentials and release Ca after stimulation, thus inducing certain forms of short-term synaptic plasticity (Werth and Thayer, 1994; Tang and Zucker, 1997; Billups and Forsythe, 2002; Levy et al., 2003; Kang et al., 2008). Removing mitochondria from axon terminals results in aberrant synaptic transmission likely due to insufficient ATP supply or altered Ca transients (Stowers et al., 2002; Guo et al., 2005; Ma et al., 2009). Neurons are polarized cells consisting of a relatively small cell body, dendrites with multiple branches and elaborate arbors, and a thin axon that can extend up to a meter long in some peripheral nerves. Due to these extremely varied morphological features, neurons face exceptional challenges to maintain energy homeostasis. Neurons require specialized mechanisms to efficiently distribute mitochondria to far distal areas where energy is in high demand, such as synaptic terminals, active growth cones, and axonal branches (Fig. 1; Morris and Hollenbeck, 1993; Ruthel and Hollenbeck, 2003). Axonal branches and synapses undergo dynamic remodeling during neuronal development and in response to synaptic activity, thereby changing mitochondrial trafficking and distribution. Neurons are postmitotic cells surviving for the lifetime of the organism. A mitochondrion needs to be removed when it becomes aged or dysfunctional. Mitochondria also alter their motility and distribution under certain stress conditions or when their integrity is impaired (Miller and Sheetz, 2004; Chang and Reynolds, 2006; Cai et al., 2012). Therefore, efficient regulation of mitochondrial trafficking and anchoring is essential to: (1) recruit and redistribute mitochondria to meet altered metabolic requirements; and (2) remove aged and damaged mitochondria and replenish healthy ones at distal terminals. Research into neuronal regulation of mitochondrial trafficking and anchoring is thus a very important frontier in neurobiology. This review article focuses on new mechanistic insight into the regulation of microtubule (MT)-based mitochondrial trafficking and anchoring and provides an updated overview of how mitochondrial motility influences neuronal growth, synaptic function, and mitochondrial quality control. Additional insight and overviews from different perspectives can be found in other in-depth reviews (Frederick and Shaw, 2007; Morfini et al., 2009; Hirokawa et al., 2010; MacAskill and Kittler, 2010; Schon and Przedborski, 2011; Court and Coleman, 2012; Saxton and Hollenbeck, 2012; Sheng and Cai, 2012; Birsa et al., 2013; Lovas and Wang, 2013; Schwarz, 2013).