Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons

Cioni, Jean-Michel; Lin, Julie Qiaojin; Holtermann, Anne V.; Koppers, Max; Jakobs, Maximilian Ah; Azizi, Afnan; Turner-Bridger, Benita; Shigeoka, Toshiaki; Franze, Kristian; Harris, William A.; Holt, Christine

doi:10.1016/j.cell.2018.11.030

Cited by 351 publications

(436 citation statements)

References 69 publications

(97 reference statements)

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“…S2e) 2Btubwt transport complexes was 0.57 m/s ( Fig. 2d) which matches the reported velocity for KIF3ABK in cells 25 and in vitro 26 and also the reported velocities for axonally localised RNAs in cultured neurons 9,27 . and a C-terminally localised Tau-like microtubule binding site 30 , could function as recruitment factor for KIF3ABK.…”

Section: Resultssupporting

confidence: 88%

A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs

Baumann

Komissarov

Gili

et al. 2019

Preprint

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Through the asymmetric distribution of mRNAs cells spatially regulate gene expression to create cytoplasmic domains with specialized functions. In mammalian neurons, mRNA localization is required for essential processes as cell polarization, migration and synaptic plasticity underlying long-term memory formation. The essential components driving cytoplasmic mRNA transport in neurons and mammalian cells are not known. Here, we report the first reconstitution of a mammalian mRNA transport system revealing that the tumour suppressor adenomatous polyposis coli (APC) forms stable complexes with the axonally localised -actin and 2B-tubulin mRNAs which are linked to a heterotrimeric kinesin-2 via the cargo adaptor KAP3. APC activates kinesin-2 and both proteins are sufficient to drive specific transport of defined mRNA packages. Guanine-rich sequences located in 3'UTRs of axonal mRNAs increase transport efficiency and balance the access of different mRNAs to the transport system. Our findings reveal for the first time a minimal set of proteins capable of driving kinesin-based, mammalian mRNA transport.Microtubule binding proteins as APC often function as catalysators for microtubule recruitment and processive movement of kinesins 28,29 . APC, harbouring an N-terminally localised KAP3 binding site 14 Fig.

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Section: Resultssupporting

confidence: 88%

A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs

Baumann

Komissarov

Gili

et al. 2019

Preprint

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“…Although it has been well-established that local translation occurs in axons and growth cones, we do not know where this translation occurs within these neuronal compartments. One recent study demonstrated that late endosomes are a platform for local translation within axons (38). Here we add to our knowledge about platforms for local translation by demonstrating that local translation also occurs at point contacts.…”

Section: Point Contacts Are Sites Of Local Translation In Growth Conessupporting

confidence: 52%

RACK1 is required for axon guidance and local translation at growth cone point contacts

Kershner

Bumbledare

Cassidy

et al. 2019

Preprint

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Local translation regulates the formation of appropriate connectivity in the developing nervous system. However, the localization and molecular mechanisms underlying this translation within growth cones is not well understood. Receptor for activated C kinase 1 (RACK1) is a multifunctional ribosomal scaffolding protein that interacts with β-actin mRNA. We recently showed that RACK1 localizes to and regulates the formation of point contacts, which are adhesion sites that control growth cone motility. This suggests that local translation occurs at these adhesion sites that are important for axonal pathfinding, but this has not been investigated. Here, we show that RACK1 is required for BDNF-induced local translation of β-actin mRNA in growth cones. Furthermore, the ribosomal binding function of RACK1 regulates point contact formation, and axon growth and guidance. We also find that local translation of β-actin occurs at point contacts.Taken together, we show that adhesions are a targeted site of local translation within growth cones, and RACK1 is critical to the formation of point contacts and appropriate neural development.These data provide further insight into how and where local translation is regulated, and thereby leads to appropriate connectivity formation in the developing nervous system.

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“…The cell body is also the site of the majority of protein synthesis in neurons. While mRNA and protein transport from the cell body to organelles in the axon can contribute to the replenishment of mitochondrial proteins 13 , it stands to reason that moving the organelle back to the primary site of protein synthesis is an efficient mechanism for bulk mitochondrial protein turnover. Our proteomics data support this as mitochondria isolated from mutants that lack mitochondrial retrograde transport show a substantial reduction in approximately a third of their mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria, 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.…”

Section: Introductionmentioning

confidence: 99%

Retrograde mitochondrial transport is essential for mitochondrial homeostasis in neurons

Mandal

Pinter

Mosqueda

et al. 2019

Preprint

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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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Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons

Cited by 351 publications

References 69 publications

A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs

A reconstituted mammalian APC-kinesin complex selectively transports defined packages of mRNAs

RACK1 is required for axon guidance and local translation at growth cone point contacts

Retrograde mitochondrial transport is essential for mitochondrial homeostasis in neurons

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