In neurons, mitochondria are transported by molecular motors throughout the cell to form and maintain functional neural connections. These organelles have many critical functions in neurons and are of high interest as their dysfunction is associated with disease. While the mechanics and impact of anterograde mitochondrial movement toward axon terminals are beginning to be understood, the frequency and function of retrograde (cell body directed) mitochondrial transport in neurons are still largely unexplored. While existing evidence indicates that some mitochondria are retrogradely transported for degradation in the cell body, the precise impact of disrupting retrograde transport on the organelles and the axon was unknown. Using long-term, in vivo imaging, we examined mitochondrial motility in zebrafish sensory and motor axons. We show that retrograde transport of mitochondria from axon terminals allows replacement of the axon terminal population within a day. By tracking these organelles, we show that not all mitochondria that leave the axon terminal are degraded; rather, they persist over several days. Disrupting retrograde mitochondrial flux in neurons leads to accumulation of aged organelles in axon terminals and loss of cell body mitochondria. Assays of neural circuit activity demonstrated that disrupting mitochondrial transport and function has no effect on sensory axon terminal activity but does negatively impact motor neuron axons. Taken together, our work supports a previously unappreciated role for retrograde mitochondrial transport in the maintenance of a homeostatic distribution of mitochondria in neurons and illustrates the downstream effects of disrupting this process on sensory and motor circuits. SIGNIFICANCE STATEMENT Disrupted mitochondrial transport has been linked to neurodegenerative disease. Retrograde transport of this organelle has been implicated in turnover of aged organelles through lysosomal degradation in the cell body. Consistent with this, we provide evidence that retrograde mitochondrial transport is important for removing aged organelles from axons; however, we show that these organelles are not solely degraded, rather they persist in neurons for days. Disrupting retrograde mitochondrial transport impacts the homeostatic distribution of mitochondria throughout the neuron and the function of motor, but not sensory, axon synapses. Together, our work shows the conserved reliance on retrograde mitochondrial transport for maintaining a healthy mitochondrial pool in neurons and illustrates the disparate effects of disrupting this process on sensory versus motor circuits.
Mitochondrial transport in neurons is essential for forming and maintaining axonal projections. While much is known about anterograde mitochondrial movement, the function of retrograde mitochondrial motility in neurons was unknown. We investigated the dynamics and utility of retrograde mitochondrial transport. Using long-term tracking of mitochondria in vivo, we found mitochondria in axon terminals turnover within hours via retrograde transport. Mitochondria do not return to the cell body solely for degradation; rather, mitochondria use bidirectional transport to redistribute themselves throughout the neuron. Disruption of retrograde mitochondrial transport severely depletes the cell body of mitochondria and impacts mitochondrial health throughout the cell.Altered mitochondrial health correlates with decreased synaptic activity. Using proteomics, we provide evidence that retrograde mitochondrial movement functions to maintain the organelle's proteome. Together, our work demonstrates that mitochondrial retrograde transport is essential for the maintenance of a homeostatic population of mitochondria in neurons and consequently effective synaptic activity through promoting mitochondrial protein turnover. KeywordsMitochondria, Axonal Transport, Cytoplasmic dynein, Mitochondrial protein import, Retrograde transport, Dynactin, Actr10, p150 glued regulation of local translation 13,14 . Therefore, maintaining a healthy pool of mitochondria, particularly in distal compartments of the neuron, is critical for the health and maintenance of functional neural circuits. While much is known about how damaged mitochondria are cleared from this region [15][16][17] , less is known about how populations of healthy mitochondria are maintained in neurons over their lifetime.Mitochondrial maintenance is complicated by the fact that this organelle requires more than a thousand proteins for optimal health and function. While mitochondria maintain their own genome 18-20 , which includes genes encoding 13 proteins in humans, the bulk of the proteins important for the function and maintenance of this organelle are synthesized from genes encoded in the nucleus 21,22 . These proteins have diverse half-lives, ranging from hours to weeks 23,24 . Once generated, mitochondrial proteins translocate to the correct compartment within the organelle through well-described mitochondrial protein import pathways 25 . However, while we know how proteins are incorporated into the organelle, how they are brought to the organelle prior to import, particularly in distal compartments, is largely unknown. While transport of proteins and/or mRNAs could be sufficient to replenish a number of mitochondrial proteins, it would require active transport of individual components to organelles which can be a meter from the cell body in humans. Given the number of mitochondrial proteins, the rapid turnover rates of a subset of them, and the distance from the cell body to distal neuronal compartments, active transport of each individual protein would be energy intensive ...
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