Mechanics of mitochondrial motility in neurons
Introduction
Neurons are morphologically complex, long-lived, and energetically expensive [1]. The vast majority of ATP production in neurons is accomplished by mitochondrial oxidative phosphorylation [2]. Neuronal size, variable activity levels, and age pose three major challenges for proper coordination of mitochondrial localization with energy demand. First, synapses are thought to be the primary sites of energy consumption in neurons [1], and complex, extended neuronal morphologies necessitate distribution of mitochondria to synapses far-removed from the cell body. Second, mitochondria must be precisely positioned near active synapses in order to sustain neuronal activity [3••] (see Box 1), and synaptic activity patterns can fluctuate over various temporal and spatial scales. Finally, oxidative phosphorylation is associated with the production of reactive oxygen species that can cause mitochondrial damage [4]. Postmitotic neurons must therefore employ mitochondrial quality control mechanisms in order to maintain mitochondrial health over the course of an entire lifetime. Thus, neurons have to maintain mitochondrial networks that are at once stable and tunable, capable of supplying energy to distant synapses for tens of years while also adapting to fluctuating energy demands.
One way to address these issues is to continually remodel and rebuild the mitochondrial network, and indeed the half-life for mitochondria in brain tissue (∼30 days) is several orders of magnitude shorter than the lifespan of a human neuron [5, 6]. The global dynamic distribution of mitochondria within a cell emerges from the interplay among four major processes: mitochondrial biogenesis, mitophagy, fission and fusion, and motility [7, 8, 9, 10, 11, 12] (Figure 1). These processes maintain a stable but tunable distribution of healthy mitochondria if they are appropriately regulated and balanced. Mitophagy of damaged mitochondria must be balanced with biogenesis of new mitochondria in order to maintain a stable mitochondrial volume. Fission must be balanced with fusion in order to maintain stable mitochondrial morphologies. Anterograde transport away from the cell body must be balanced by retrograde transport in order to maintain stable mitochondrial distributions. How are these processes properly balanced over large spatial and temporal scales in neurons? And how are they modulated in response to changing synaptic activity patterns? Mechanisms for the spatial and temporal control of biogenesis, fission and fusion, and mitophagy have not been extensively studied in neurons, with a few notable exceptions [13•, 14•]. Thus, here I focus on the spatiotemporal integration of molecular and mechanical mechanisms that control mitochondrial motility.
Section snippets
Mitochondria-motor ensembles are dynamic mechanical systems
Mitochondria in neurons are transported on microtubule filaments by plus end directed kinesin-1/KIF5 and minus end directed cytoplasmic dynein motors [15], hereafter referred to as kinesin and dynein, respectively. Time-lapse imaging of mitochondria in cultured neurons has shown that approximately 10–50% of mitochondria are motile, and the rates of anterograde (away from the cell soma) and retrograde (back toward the soma) transport are roughly equivalent [16, 17, 18•, 19•]. What determines
Retrograde and anterograde transport in axons and dendrites: which way to go?
Mitochondria are densely distributed within axons and dendrites, and anterograde and retrograde transport rates are roughly balanced in both compartments [17, 19•]. How is this balance achieved? The direction of movement of a particular mitochondrion depends on three parameters: microtubule orientation, the relative number of attached kinesin and dynein molecules, and the extent to which these bound motors are engaged, or actively driving transport along microtubules [22]. Thus, complete
Activity-dependent regulation of adaptor proteins
Once mitochondria are sorted into axons and dendrites, they then have to be localized to synapses or other subcellular regions with high energy demands. One general strategy for enriching mitochondria in a particular part of the cell is to locally regulate adaptor proteins and reduce either mitochondria-motor attachment or motor engagement. Several signaling pathways converge on the Miro-Milton complex [18•, 37•, 46, 47, 48, 49••], and calcium signaling, in particular, is thought to localize
Moving beyond motility: mitochondrial biogenesis, fission and fusion, and mitophagy
In addition to moving along cytoskeletal filaments, mitochondria grow, divide and fuse, and are turned over in an active fashion. The molecular and biophysical mechanisms that control each of these processes are increasingly well characterized (reviewed in [7, 8, 9, 10, 11, 12]). Moreover, mutations that disrupt mitochondrial biogenesis, fission, fusion, or mitophagy are associated with a wide range of neurodegenerative disorders. However, mechanisms for the spatiotemporal regulation of these
Concluding remarks
A comprehensive, systems level picture of the mechanisms that govern mitochondrial motility in neurons will require, first, further characterization of the molecular mechanisms that regulate kinesin and dynein attachment and engagement, and second, additional investigation of interactions likely to mechanically oppose movement. In addition to delineating molecular and mechanical mechanisms, it is necessary to understand how motility is regulated in space and time — in axons versus dendrites,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I would like to thank Tom Clandinin, Natalie Dye, Vilaiwan Fernandes and Steph Weber for comments on the manuscript. Financial support was provided by NIH F32 grant #5F32EY023125-03.
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