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Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration

Key Points

  • Mitochondria are essential for neuronal function and survival. Mitochondria are commonly found in synaptic terminals, where they help to maintain neurotransmission by producing ATP and buffering Ca2+.

  • Mitochondrial transport and distribution in neurons is efficiently regulated in response to changes in neuronal activity and various physiological and pathological states.

  • Neuronal mitochondria undergo dynamic and bidirectional transport along neuronal processes, frequently changing direction, pausing or switching to persistent docking.

  • These complex mitochondrial mobility patterns are a result of mitochondrial coupling to anterograde kinesin motors of the KIF5 family and to the retrograde motor dynein, as well as to docking and anchoring machineries, including syntaphilin.

  • Mitochondria attach to the motors by associating with their respective motor adaptor proteins and mitochondrial receptors. These motor–adaptor–receptor complexes ensure targeted trafficking of mitochondria and precise regulation of their mobility.

  • The KIF5–Milton–MIRO complex constitutes a mitochondrial transport machinery, through which a MIRO Ca2+-sensing pathway mediates the suppression of mitochondrial mobility in response to increased action potential firing rates or the activation of glutamate receptors.

  • Syntaphilin acts as a 'static anchor' for axonal mitochondria. Deleting the syntaphilin gene resulted in a robust increase in the percentage of mobile axonal mitochondria relative to wild-type neurons.

  • Elaborate mitochondrial quality-control systems maintain mitochondrial integrity and function. These include transport, fusion, fission and turnover via mitophagy and constitute an interdependent system of mitochondrial dynamics.

  • It is well documented that mitochondrial dysfunction, changes in mitochondrial dynamics and mobility, and perturbation of mitochondrial turnover are involved in the pathology of some major neurodegenerative and neurological disorders.

  • Identification of the molecules involved in linking mitochondrial transport, fusion, fission and mitophagy will advance our understanding of the cellular mechanisms that regulate mitochondrial quality control and thus human neurodegenerative diseases.

Abstract

Mitochondria have a number of essential roles in neuronal function. Their complex mobility patterns within neurons are characterized by frequent changes in direction. Mobile mitochondria can become stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Research into the mechanisms that regulate mitochondrial transport is thus an important emerging frontier.

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Figure 1: Mitochondrial transport in neurons.
Figure 2: KIF5-driven mitochondrial transport.
Figure 3: Mitochondrial docking and synaptic homeostasis.

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Acknowledgements

The authors thank M. Davis for editing and other members of the Sheng laboratory for their assistance and discussion. This work was supported by the Intramural Research Program of the US National Institute of Neurological Disorder and Stroke (NINDS), US National Institutes of Health (NIH) (Z.-H.S.) and the NIH Pathway to Independence Award K99 (Q.C.).

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Supplementary Information S1

Representative time-lapse images of axonal mitochondrial motility in wild-type cultured hippocampal neurons. (PDF 90 kb)

Supplementary Information S1 (movie) (MOV 13625 kb)

Supplementary Information S2

Representative time-lapse images of axonal mitochondrial motility in cultured hippocampal neurons from the syntaphilin−/− mice. (PDF 106 kb)

Supplementary Information S2 (movie) (MOV 12310 kb)

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Glossary

Nodes of Ranvier

Regularly spaced gaps in the myelin sheath that surrounds myelinated axons. They expose the axonal plasma membrane to the extracellular fluid. Nodes of Ranvier contain large numbers of voltage-gated ion channels and thus enable conduction of the action potential.

Autophagy–lysosomal system

A primary cellular route for the breakdown of organelles and the degradation of cytoplasmic components. Following the sequestration of organelles and cytoplasm within a double-membrane-bound vacuole (autophagosome), fusion with lysosomes occurs. Lysosomal hydrolases in these 'autolysosomes' degrade their contents.

EF hand

A Ca2+-binding domain that was originally identified in parvalbumin. EF hands are also known as helix–turn–helix domains.

Small interfering RNA

(siRNA). A sequence-specific gene-silencing tool used in RNA interference. siRNAs are short fragments of synthetic double-stranded RNA with 21–23 pairs of nucleotides that have sequence specificity to the gene of interest (the target). These small double-stranded RNAs trigger degradation of the target RNA, thereby creating a partial loss-of-function.

RNA interference

(RNAi). A method by which double-stranded RNA that is encoded in an exogenous vector can be used to interfere with normal RNA processing, causing rapid degradation of the endogenous RNA and thereby precluding translation. This provides a simple way of studying the effects of the absence of a gene product in simple organisms and cells.

Processivity

Motor proteins move stepwise along microtubules without detachment over long distances at the expense of ATP. This movement, termed hand-over-hand motility, is based on the coordinated action of two motor heads that bind one after another to microtubules. This mechanism requires precise coordination of the microtubule affinity of the two motor domains.

Saltatory mobility patterns

The complex nature of mitochondrial transport along neuronal processes, whereby mitochondria move bidirectionally, pause and start moving again, slow down and speed up, and frequently change direction.

Na+/K+ ATPases

Also known as Na+/K+ pumps, these membrane proteins use ATP hydrolysis to move Na+ and K+ in opposite directions across the plasma membrane. They are responsible for maintaining transmembrane concentration gradients for both Na+ and K+ and have a particularly important role in enabling neurons to respond to stimuli and transmit impulses.

Short-term facilitation

A transient increase in synaptic strength occurs when two or more action potentials invade the presynaptic terminal in close succession or as a result of a high-frequency burst of presynaptic action potentials. Facilitation results in more neurotransmitter being released in response to each succeeding action potential owing to prolonged elevation of presynaptic Ca2+ levels following synaptic activity.

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Sheng, ZH., Cai, Q. Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13, 77–93 (2012). https://doi.org/10.1038/nrn3156

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